Pyridopyrazine compounds and uses thereof

ABSTRACT

Disclosed herein, inter alia, are pyridopyrazines and methods of using the same.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/523,412, filed on Jun. 22, 2017, which is incorporated herein byreference in its entirety and for all purposes.

BACKGROUND

In the United States, the lifetime risk of developing cancer is roughly42% for men and 38% for women. The lifetime risk of dying from cancer is23% for men and 19% for women in the United States. New cancertreatments and preventatives are needed. Disclosed herein, inter alia,are solutions to these and other problems in the art.

SUMMARY

In an aspect is provided a compound having the formula:

Ring A is an aryl or heteroaryl.

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹ ₃, —OCX¹ ₃,—OCH₂X¹, —OCHX¹ ₂, —N₃, —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. Two adjacent R¹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

z1 is an integer from 0 to 5.

Ring B is an aryl or heteroaryl.

R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, —CN, —SO_(n2)R^(2D), —SO_(v2)NR^(2A)R^(2B),—NHC(O)NR^(2A)R^(2B), —N(O)_(m2), —NR^(2A)R^(2B), —C(O)R^(2C),—C(O)—OR^(2C), —C(O)NR^(2A)R^(2B), —OR^(2D), —NR^(2A)SO₂R^(2D),—NR^(2A)C(O)R^(2C), —NR^(2A)C(O)OR^(2C), —NR^(2A)OR^(2C), —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. Two adjacent R² substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

z2 is an integer from 0 to 5.

R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃,—OCH₂X³, —OCHX³ ₂, —N₃, —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), —OR^(3A), —NR^(3A)SO₂R^(3B),—NR^(3A)C(O)R^(3B), —NR^(3A)C(O)OR^(3B), —NR^(3A)OR^(3B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

L is independently a bond or —N(R⁵)—.

R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —C(O)R^(5A),—C(O)OR^(5A), —C(O)NR^(5A)R^(5B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R⁶ is independently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —C(O)R^(6A),—C(O)OR^(6A), —C(O)NR^(6A)R^(6B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R⁷ is independently hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃,—OCH₂X⁷, —OCHX⁷ ₂, —N₃, —CN, —SO_(n7)R^(7A), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7A),—C(O)OR^(7A), —C(O)NR^(7A)R^(7B), —OR^(7A), —NR^(7A)SO₂R^(7B),—NR^(7A)C(O)R^(7B), —NR^(7A)C(O)OR^(7B), —NR^(7A)OR^(7B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁸ is independently hydrogen, halogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, —OCX⁸ ₃,—OCH₂X⁸, —OCHX⁸ ₂, —N₃, —CN, —SO_(n8)R^(8A), —SO_(v8)NR^(8A)R^(8B),—NHC(O)NR^(8A)R^(8B), —N(O)_(m8), —NR^(8A)R^(8B), —C(O)R^(8A),—C(O)OR^(8A), —C(O)NR^(8A)R^(8B), —OR^(8A), —NR^(8A)SO₂R^(8B),—NR^(8A)C(O)R^(8B), —NR^(8A)C(O)OR^(8B), —NR^(8A)OR^(8B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

Each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),R^(3A), R^(3B), R^(4A), R^(4B), R^(5A), R^(5B), R^(6A), R^(6B), R^(7A),R^(7B), R^(8A), and, R^(8B) is independently hydrogen, —CX₃, —COOH,—CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(2A) and R^(2B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(3A) and R^(3B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(5A) andR^(5B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(6A) and R^(6B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(8A) and R^(8B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

Each X, X¹, X², X³, X⁴, X⁵, X⁶, X⁷, and X⁸ is independently —F, —Cl,—Br, or —I.

n1, n2, n3, n7, and n8 are independently an integer from 0 to 4.

m1, m2, m3, m7, m8, v1, v2, v3, v7, and v8 are independently 1 or 2.

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In an aspect is provided a method of treating cancer, the methodincluding administering to a subject in need thereof an effective amountof a compound described herein.

In an aspect is provided a method of inhibiting cell proliferation, themethod including contacting the cell with a compound described herein.

DETAILED DESCRIPTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain.Examples of saturated hydrocarbon radicals include, but are not limitedto, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, S, B, As, or Si), and wherein thenitrogen and sulfur atoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N,P, S, B, As, or Si) may be placed at any interior position of theheteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Heteroalkyl is an uncyclizedchain. Examples include, but are not limited to: —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—S—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CHO—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g.,O, N, P, S, B, As, or Si). A heteroalkyl moiety may include twooptionally different heteroatoms (e.g., O, N, P, S, B, As, or Si). Aheteroalkyl moiety may include three optionally different heteroatoms(e.g., O, N, P, S, B, As, or Si). A heteroalkyl moiety may include fouroptionally different heteroatoms (e.g., O, N, P, S, B, As, or Si). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, P, S, B, As, or Si). A heteroalkyl moiety may include up to8 optionally different heteroatoms (e.g., O, N, P, S, B, As, or Si).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂₋. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R‘- and —R’C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,”“heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R′R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C(O)NR″NR″′R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″ ″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″ ″ group when more than one of these groups is present. When R′and R″ are attached to the same nitrogen atom, they can be combined withthe nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R′R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″ ″, —NR—C(NR′R″)═NR″′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″,—NR′C(O)NR″NR″′R″ ″, —CN, —NO₂, —R, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, and R″ ″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″ ″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R″R″′)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B),and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂,—CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂F,—OCH₂I, —N₃, unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), and(B) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered),substituted with at least one substituent selected from:

-   -   (i) oxo,    -   halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,        —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂,        —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,        —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,        —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,        —OCH₂Br, —OCH₂F, —OCH₂I, —N₃, unsubstituted alkyl (e.g., C₁-C₂₀,        C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted        heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8        membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or        4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,        C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3        to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6        membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted        aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted        heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9        membered, or 5 to 6 membered), and    -   (ii) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or        C₁-C₂), heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2        to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3        membered, or 4 to 5 membered), cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,        C₃-C₆, C₄-C₆, or C₅-C₆), heterocycloalkyl (e.g., 3 to 10        membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4        to 5 membered, or 5 to 6 membered), aryl (e.g., C₆-C₁₂, C₆-C₁₀,        or phenyl), or heteroaryl (e.g., 5 to 12 membered, 5 to 10        membered, 5 to 9 membered, or 5 to 6 membered), substituted with        at least one substituent selected from:        -   (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,            —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,            —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        -   —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,            —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I,            —N₃, unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,            C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2            to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6            membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5            membered), unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,            C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl            (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4            to 6 membered, 4 to 5 membered, or 5 to 6 membered),            unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or            unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10            membered, 5 to 9 membered, or 5 to 6 membered), and        -   (b) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or            C₁-C₂), heteroalkyl (e.g., 2 to 20 membered, 2 to 12            membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered,            2 to 3 membered, or 4 to 5 membered), cycloalkyl (e.g.,            C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), heterocycloalkyl            (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4            to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl            (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or heteroaryl (e.g., 5 to            12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6            membered), substituted with at least one substituent            selected from: oxo,        -   halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂,            —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,            —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N H₂, —NHNH₂, —ONH₂,            —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,            —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,            —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —N₃,            unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆,            C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 20            membered, 2 to 12 membered, 2 to 8 membered, 2 to 6            membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5            membered), unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,            C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl            (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4            to 6 membered, 4 to 5 membered, or 5 to 6 membered),            unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or            unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10            membered, 5 to 9 membered, or 5 to 6 membered).

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryl eneis a substituted or unsubstituted 5 to 10 membered heteroaryl ene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

In embodiments, a substituted or unsubstituted moiety (e.g., substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted aryl ene, and/orsubstituted or unsubstituted heteroaryl ene) is unsubstituted (e.g., isan unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, unsubstituted alkylene, unsubstitutedheteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted aryl ene, and/or unsubstitutedheteroaryl ene, respectively). In embodiments, a substituted orunsubstituted moiety (e.g., substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, and/or substituted or unsubstituted heteroaryl ene) issubstituted (e.g., is a substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkylene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,wherein if the substituted moiety is substituted with a plurality ofsubstituent groups, each substituent group may optionally be different.In embodiments, if the substituted moiety is substituted with aplurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one size-limited substituentgroup, wherein if the substituted moiety is substituted with a pluralityof size-limited substituent groups, each size-limited substituent groupmay optionally be different. In embodiments, if the substituted moietyis substituted with a plurality of size-limited substituent groups, eachsize-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one lower substituent group,wherein if the substituted moiety is substituted with a plurality oflower substituent groups, each lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of lower substituent groups, each lower substituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkyl ene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groupsselected from substituent groups, size-limited substituent groups, andlower substituent groups; each substituent group, size-limitedsubstituent group, and/or lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent group isdifferent.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)-for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. The disease may be a cancer. Insome further instances, “cancer” refers to human cancers and carcinomas,sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solidand lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, lymphomas, carcinomas and sarcomas. Exemplary cancers that maybe treated with a compound or method provided herein include braincancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectalcancer, pancreatic cancer, cervical cancer, gastric cancer, ovariancancer, lung cancer, and cancer of the head. Exemplary cancers that maybe treated with a compound or method provided herein include cancer ofthe thyroid, endocrine system, brain, breast, cervix, colon, head &neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma,ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer,pancreatic cancer. Additional examples include, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma,glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primarythrombocytosis, primary macroglobulinemia, primary brain tumors, cancer,malignant pancreatic insulanoma, malignant carcinoid, urinary bladdercancer, premalignant skin lesions, testicular cancer, lymphomas, thyroidcancer, neuroblastoma, esophageal cancer, genitourinary tract cancer,malignant hypercalcemia, endometrial cancer, adrenal cortical cancer,neoplasms of the endocrine or exocrine pancreas, medullary thyroidcancer, medullary thyroid carcinoma, melanoma, colorectal cancer,papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

As used herein, the term “lymphoma” refers to a group of cancersaffecting hematopoietic and lymphoid tissues. It begins in lymphocytes,the blood cells that are found primarily in lymph nodes, spleen, thymus,and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma andHodgkin's disease. Hodgkin's disease represents approximately 15% of alldiagnosed lymphomas. This is a cancer associated with Reed-Sternbergmalignant B lymphocytes. Non-Hodgkin's lymphomas (NHL) can be classifiedbased on the rate at which cancer grows and the type of cells involved.There are aggressive (high grade) and indolent (low grade) types of NHL.Based on the type of cells involved, there are B-cell and T-cell NHLs.Exemplary B-cell lymphomas that may be treated with a compound or methodprovided herein include, but are not limited to, small lymphocyticlymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zonelymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell)lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt'slymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, orprecursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that maybe treated with a compound or method provided herein include, but arenot limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma,anaplastic large cell lymphoma, mycosis fungoides, and precursorT-lymphoblastic lymphoma.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypemephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

The terms “treating”, or “treatment” refers to any indicia of success inthe therapy or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of aninjury, pathology, condition, or disease. In embodiments, treating ispreventing. In embodiments, treating does not include preventing.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

A “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist. The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington; The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,intraperitoneal, intramuscular, intralesional, intrathecal, intranasalor subcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route, including parenteral and transmucosal (e.g., buccal,sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal)compatible with the preparation. Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

“Co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of theinvention can be administered alone or can be coadministered to thepatient. Coadministration is meant to include simultaneous or sequentialadministration of the compounds individually or in combination (morethan one compound). Thus, the preparations can also be combined, whendesired, with other active substances (e.g. to reduce metabolicdegradation). The compositions of the present invention can be deliveredtransdermally, by a topical route, or formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization. In embodiments,the cell is a cancer cell. In embodiments, the cell is a melanoma cell.In In embodiments, the cell is a prostate cell. In embodiments, the cellis a prostate cancer cell. In embodiments, the cell is a lung cancercell cell. In embodiments, the cell is a non-small lung cancer cell.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

The term “modulator” refers to a composition that increases or decreasesthe level or activity of a target molecule or the function of a targetmolecule or the physical state of the target of the molecule.

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, as applied to the effects of amodulator on a target protein, to modulate means to change by increasingor decreasing a property or function of the target molecule or theamount of the target molecule.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. aprotein associated disease) means that the disease (e.g. cancer) iscaused by (in whole or in part), or a symptom of the disease is causedby (in whole or in part) the substance or substance activity orfunction.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity or protein function, aberrant refersto activity or function that is greater or less than a normal control orthe average of normal non-diseased control samples. Aberrant activitymay refer to an amount of activity that results in a disease, whereinreturning the aberrant activity to a normal or non-disease-associatedamount (e.g. by administering a compound or using a method as describedherein), results in reduction of the disease or one or more diseasesymptoms.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

“Anti-cancer agent” or “anti-cancer drug” is used in accordance with itsplain ordinary meaning and refers to a composition (e.g. compound, drug,antagonist, inhibitor, modulator) having antineoplastic properties orthe ability to inhibit the growth or proliferation of cells. In someembodiments, an anti-cancer agent is a chemotherapeutic. In someembodiments, an anti-cancer agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcancer. Examples of anti-cancer agents include, but are not limited toMEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040,PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973,ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733,PD318088, AS703026, BAY 869766), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomusitne, semustine, streptozocin), triazenes (decarbazine)),anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine,fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog(e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel,docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.),antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin,epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin,etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin,carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea(e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide),epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin,doxorubicin, bleomycin), inhibitors of mitogen-activated protein kinasesignaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886,SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002), mTORinhibitors, antibodies (e.g., rituxan), 5-aza-2′-deoxycytidine,doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®),geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG),bortezomib, trastuzumab, anastrozole; angiogenesis inhibitors;antiandrogen, antiestrogen; antisense oligonucleotides; apoptosis genemodulators; apoptosis regulators; BCR/ABL antagonists; bFGF inhibitor;bicalutamide; camptothecin derivatives; casein kinase inhibitors (ICOS);clomifene analogues; cytarabine dacliximab; dexamethasone; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; finasteride; fludarabine; fluorodaunorunicinhydrochloride; gadolinium texaphyrin; gallium nitrate; gelatinaseinhibitors; gemcitabine; glutathione inhibitors; hepsulfam;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; letrozole;leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; oxaliplatin; panomifene; pentrozole;platinum complex; platinum compounds; prednisone; proteasome inhibitors;protein kinase C inhibitor; protein tyrosine phosphatase inhibitors;purine nucleoside phosphorylase inhibitors; ras farnesyl proteintransferase inhibitors; ras inhibitors; ras-GAP inhibitor; stem cellinhibitor; stem-cell division inhibitors; stromelysin inhibitors;synthetic glycosaminoglycans; tamoxifen methiodide; telomeraseinhibitors; thyroid stimulating hormone; translation inhibitors;tyrosine kinase inhibitors; urokinase receptor antagonists; steroids(e.g., dexamethasone), finasteride, aromatase inhibitors,gonadotropin-releasing hormone agonists (GnRH) such as goserelin orleuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, dactinomycin, doxorubicin, epirubicin, topotecan,itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine,sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine,vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors,epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic(e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™),lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™),afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714,TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804,OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569,CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626),sorafenib, imatinib, sunitinib, dasatinib, pyrrolo benzodiazepines (e.g.tomaymycin), carboplatin, CC-1065 and CC-1065 analogs includingamino-CBIs, nitrogen mustards (such as chlorambucil and melphalan),dolastatin and dolastatin analogs (including auristatins: eg. monomethylauristatin E), anthracycline antibiotics (such as doxorubicin,daunorubicin, etc.), duocarmycins and duocarmycin analogs, enediynes(such as neocarzinostatin and calicheamicins), leptomycin derivatives,maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate,mitomycin C, taxoids, vinca alkaloids (such as vinblastine andvincristine), epothilones (e.g. epothilone B), camptothecin and itsclinical analogs topotecan or irinotecan, Docetaxel, Paclitaxel,Platinum agents (cisplatin, carboplatin), Vinorelbine, Capecitabine,Liposomal doxorubicin, Gemcitabine, Mitoxantrone, Ixabepilone,Albumin-bound paclitaxel (nab-paclitaxel, Abraxane), Eribulin,Toremifene, Fulvestrant, Letrozole, Anastrozole, Exemestane, Megestrol,Trastuzumab, Pertuzumab, Ado-trastuzumab emtansine, Lapatinib,Palbociclib, ribociclib, and Everolimus.

II. Compounds

In an aspect is provided a compound having the formula:

R¹⁰¹ is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted unsubstituted heteroaryl, or —N(R⁴)-L¹-R¹⁰².

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

L¹ is independently a bond, —C(O)-L-, —C(O)—, —C(O)N(R⁵)—, —C(O)CH₂—,—C(O)CH₂N(R⁵)—, —C(O)N(R⁵)CH₂—, —C(S)-L-, —C(S)—, —C(S)N(R⁵)—,—C(S)CH₂—, —C(S)CH₂N(R⁵)—, or —C(S)N(R⁵)CH₂—, S(O)₂—;

L is independently a bond or —N(R⁵)—.

R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —C(O)R^(5A),—C(O)OR^(5A), —C(O)NR^(5A)R^(5B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R¹⁰² is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted unsubstituted heteroaryl, or -(Ring A)-(R¹)_(z1).

R¹⁰³ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or-L²-(Ring B)-(R²)_(z2).

L² is independently —N(R⁶)—, —S—, or —O—. In embodiments, L² is not —S—.In embodiments, L² is not —O—.

R⁶ is independently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —C(O)R^(6A),—C(O)OR^(6A), —C(O)NR^(6A)R^(6B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

Ring B is an aryl or heteroaryl.

R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, —CN, —SO_(n2)R^(2D), —SO_(v2)NR^(2A)R^(2B),—NHC(O)NR^(2A)R^(2B), —N(O)_(m2), —NR^(2A)R^(2B), —C(O)R^(2C),—C(O)—OR^(2C), —C(O)NR^(2A)R^(2B), —OR^(2D), —NR^(2A)SO₂R^(2D),—NR^(2A)C(O)R^(2C), —NR^(2A)C(O)OR^(2C), —NR^(2A)OR^(2C), —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. Two adjacent R² substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

z2 is an integer from 0 to 5.

R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃,—OCH₂X³, —OCHX³ ₂, —N₃, —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), —OR^(3A), —NR^(3A)SO₂R^(3B),—NR^(3A)C(O)R^(3B), —NR^(3A)C(O)OR^(3B), —NR^(3A)OR^(3B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁷ is independently hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃,—OCH₂X⁷, —OCHX⁷ ₂, —N₃, —CN, —SO_(n7)R^(7A), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B), —N(O)_(m)v, —NR^(7A)R^(7B), —C(O)R^(7A),—C(O)OR^(7A), —C(O)NR^(7A)R^(7B), —OR^(7A), —NR^(7A)SO₂R^(7B),—NR^(7A)C(O)R^(7B), —NR^(7A)C(O)OR^(7B), —NR^(7A)OR^(7B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁸ is independently hydrogen, halogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, —OCX⁸ ₃,—OCH₂X⁸, —OCHX⁸ ₂, —N₃, —CN, —SO_(n8)R^(8A), —SO_(v8)NR^(8A)R^(8B),—NHC(O)NR^(8A)R^(8B), —N(O)_(m8), —NR^(8A)R^(8B), —C(O)R^(8A),—C(O)OR^(8A), —C(O)NR^(8A)R^(8B), —OR^(8A), —NR^(8A)SO₂R^(8B),—NR^(8A)C(O)R^(8B), —NR^(8A)C(O)OR^(8B), —NR^(8A)OR^(8B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

Each R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(4A), R^(4B),R^(5A), R^(5B), R^(6A), R^(6B), R^(7A), R^(7B), R^(8A), and R^(8B) isindependently hydrogen, —CX₃, —COOH, —CONH₂, —CHX₂, —CH₂X, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(2A) and R^(2B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(3A) and R^(3B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(4A) andR^(4B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(5A) and R^(5B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(6A) and R^(6B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(7A) and R^(7B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(8A) andR^(8B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl.

Each X, X², X³, X⁴, X⁵, X⁶, X⁷, and X⁸ is independently —F, —Cl, —Br, or—I.

n2, n3, n7, and n8 are independently an integer from 0 to 4.

m2, m3, m7, m8, v2, v3, v7, and v8 are independently 1 or 2.

In embodiments, R¹⁰¹ is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —N O₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered), or —N(R⁴)-L¹-R¹⁰².

In embodiments, R¹⁰¹ is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkyl, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted aryl, or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroaryl, or—N(R⁴)-L¹-R¹⁰².

In embodiments, R¹⁰¹ is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl, or —N(R⁴)-L¹-R¹⁰².

In embodiments, R¹⁰² is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered), or -(Ring A)-(R¹)_(z1).

In embodiments, R¹⁰² is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkyl, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted aryl, or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroaryl, or -(RingA)-(R¹)_(z1).

In embodiments, R¹⁰² is hydrogen,

halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl, or -(Ring A)-(R¹)_(z1).

In embodiments, R¹⁰³ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or-L²-(Ring B)-(R²)_(z2).

In embodiments, R¹⁰³ is hydrogen, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered), or -L²-(Ring B)-(R²)_(z2).

In embodiments, R¹⁰³ is hydrogen, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkyl, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted cycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl, or substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl, or -L²-(Ring B)-(R²)_(z2).

In embodiments, R¹⁰³ is hydrogen, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl, or -L²-(RingB)-(R²)_(z2).

In embodiments, the compound has the formula:

R², Z2, Ring B, L², R³, R⁷, R⁸, and R¹⁰¹ are as described herein.

In embodiments, the compound has the formula:

R², z2, Ring B, L², R³, R⁷, R⁸, R⁴, L¹, and R¹⁰² are as describedherein.

In embodiments, the compound has the formula:

R², z2, Ring B, R⁶, R³, R⁷, R⁸, R⁴, and L are as described herein.

Ring A is an aryl or heteroaryl.

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. Two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

z1 is an integer from 0 to 5.

Each R^(1A), R^(1B), R^(1C), and R^(1D) is independently hydrogen, —CX₃,—COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

Each X¹ is independently —F, —Cl, —Br, or —I.

n1 is independently an integer from 0 to 4.

m1 and v1 are independently 1 or 2.

In an aspect is provided a compound having the formula:

Ring A is an aryl or heteroaryl.

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. Two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

z1 is an integer from 0 to 5.

Ring B is an aryl or heteroaryl.

R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, —CN, —SO_(n2)R^(2D), —SO_(v2)NR^(2A)R^(2B),—NHC(O)NR^(2A)R^(2B), —N(O)_(m2), —NR^(2A)R^(2B), —C(O)R^(2C),—C(O)—OR^(2C), —C(O)NR^(2A)R^(2B), —OR^(2D), —NR^(2A)SO₂R^(2D),—NR^(2A)C(O)R^(2C), —NR^(2A)C(O)OR^(2C), —NR^(2A)OR^(2C), —N₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. Two adjacent R² substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

z2 is an integer from 0 to 5.

R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃,—OCH₂X³, —OCHX³ ₂, —N₃, —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), —OR^(3A), —NR^(3A)SO₂R^(3B),—NR^(3A)C(O)R^(3B), —NR^(3A)C(O)OR^(3B), —NR^(3A)OR^(3B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

L is independently a bond or —N(R⁵)—.

R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —C(O)R^(5A),—C(O)OR^(5A), —C(O)NR^(5A)R^(5B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R⁶ is independently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —C(O)R^(6A),—C(O)OR^(6A), —C(O)NR^(6A)R^(6B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R⁷ is independently hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃,—OCH₂X⁷, —OCHX⁷ ₂, —N₃, —CN, —SO_(n7)R^(7A), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7A),—C(O)OR^(7A), —C(O)NR^(7A)R^(7B), —OR^(7A), —NR^(7A)SO₂R^(7B),—NR^(7A)C(O)R^(7B), —NR^(7A)C(O)OR^(7B), —NR^(7A)OR^(7B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁸ is independently hydrogen, halogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, —OCX⁸ ₃,—OCH₂X⁸, —OCHX⁸ ₂, —N₃, —CN, —SO_(n8)R^(8A), —SO_(v8)NR^(8A)R^(8B),—NHC(O)NR^(8A)R^(8B), —N(O)_(m8), —NR^(8A)R^(8B), —C(O)R^(8A),—C(O)OR^(8A), —C(O)NR^(8A)R^(8B), —OR^(8A), —NR^(8A)SO₂R^(8B),—NR^(8A)C(O)R^(8B), —NR^(8A)C(O)OR^(8B), —NR^(8A)OR^(8B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

Each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),R^(3A), R^(3B), R^(4A), R^(4B), R^(5A), R^(5B), R^(6A), R^(6B), R^(7A),R^(7B), R^(8A), and R^(8B) is independently hydrogen, —CX₃, —COOH,—CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(2A) and R^(2B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(3A) and R^(3B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(5A) andR^(5B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(6A) and R^(6B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(8A) and R^(8B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

Each X, X¹, X², X³, X⁴, X⁵, X⁶, X⁷, and X⁸ is independently —F, —Cl,—Br, or —I.

n1, n2, n3, n7, and n8 are independently an integer from 0 to 4.

m1, m2, m3, m7, m8, v1, v2, v3, v7, and v8 are independently 1 or 2.

In embodiments, the compound has the formula:

and R¹, R², R³, R⁴, R⁵, R⁶, z1, z2, Ring A, and Ring B are as describedherein.

In embodiments, the compound has the formula:

and R¹, R², z1, z2, Ring A, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

R^(1.1), R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independentlyequal to hydrogen or any value of R¹ as described herein. For example,R^(1.2) may be —CF₃. For example, R^(1.2) may be —CX¹ ₃. For example,R^(1.2) may be —Cl. For example, R^(1.2) may be halogen. For example,R^(1.3) may be —CF₃. For example, R^(1.3) may be —CX³ ₃. For example,R^(1.3) may be —F. For example, R^(1.3) may be halogen. For example,R^(1.2) may be —Cl and R^(1.3) may be —F. For example, R^(1.3) may be—SCH₃. For example, R^(1.3) may be —SCH₂CH₃. For example, R^(1.3) may be—SCH(CH₃)₂. For example, R^(1.3) may be —SC(CH₃)₃.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R^(1.2), R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.2) and R^(1.3) are as described herein.

In embodiments, the compound has the formula:

and R^(1.2) and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.2) and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.2) is as described herein.

In embodiments, the compound has the formula:

and R¹, R², z1, z2, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R¹, R², z1, and Ring A are as described herein. In embodiments, R²is independently-C(O)OCH₃. In embodiments, R² is independently—C(O)OCH₂CH₃. In embodiments, R² is independently —C(O)OCH(CH₃)₂. Inembodiments, R² is independently —C(O)OC(CH₃)₃. In embodiments, R² isindependently —NHC(O)CH₃. In embodiments, R² is independently—NHC(O)CH₂CH₃. In embodiments, R² is independently —NHC(O)CH(CH₃)₂. Inembodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

and R¹, R², z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R¹, z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R^(1.3), R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R^(1.3) and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.3) and R² are as described herein. In embodiments, R² isindependently-C(O)OCH₃. In embodiments, R² is independently—C(O)OCH₂CH₃. In embodiments, R² is independently —C(O)OCH(CH₃)₂. Inembodiments, R² is independently —C(O)OC(CH₃)₃. In embodiments, R² isindependently —NHC(O)CH₃. In embodiments, R² is independently—NHC(O)CH₂CH₃. In embodiments, R² is independently —NHC(O)CH(CH₃)₂. Inembodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

and R^(1.3) is as described herein.

In embodiments, the compound has the formula:

and R^(1.1)R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are as describedherein.

R^(2.1), R^(2.2), R^(2.3), R^(2.4), and R^(2.5) are each independentlyequal to hydrogen or any value of R² as described herein. For example,R^(2.2) may be —COOH. For example, R^(2.2) may be —COOCH₂CH₃. Forexample, R^(2.2) may be —NHCOCH₃. For example, R^(2.2) may be —OCH₃. Forexample, R^(2.3) may be —COOH. For example, R^(2.3) may be —COOCH₂CH₃.For example, R^(2.3) may be —NHCOCH₃. For example, R^(2.3) may be —OCH₃.For example, R^(2.4) may be —COOH. For example, R^(2.4) may be—COOCH₂CH₃. For example, R^(2.4) may be —NHCOCH₃. For example, R^(2.4)may be —OCH₃.

In embodiments, the compound has the formula:

and R^(2.1), R^(2.2), R^(2.3), R^(2.4), R^(2.5), R¹, z1, and Ring A areas described herein.

In embodiments, the compound has the formula:

and R^(2.3), R¹, z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R^(2.2), R¹, z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R^(2.2), R^(2.3), R^(2.4), R¹, z1, and Ring A are as describedherein.

In embodiments, the compound has the formula:

and R¹, R², R³, R⁴, R⁶, z1, z2, Ring A, and Ring B are as describedherein.

In embodiments, the compound has the formula:

and R¹, R², z1, z2, Ring A, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein. In embodiments, R² is independently—C(O)OCH₃. In embodiments, R² is independently —C(O)OCH₂CH₃. Inembodiments, R² is independently —C(O)OCH(CH₃)₂. In embodiments, R² isindependently —C(O)OC(CH₃)₃. In embodiments, R² is independently—NHC(O)CH₃. In embodiments, R² is independently —NHC(O)CH₂CH₃. Inembodiments, R² is independently —NHC(O)CH(CH₃)₂. In embodiments, R² isindependently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein. In embodiments, R² is independently—C(O)OCH₃. In embodiments, R² is independently —C(O)OCH₂CH₃. Inembodiments, R² is independently —C(O)OCH(CH₃)₂. In embodiments, R² isindependently-C(O)OC(CH₃)₃. In embodiments, R² isindependently-NHC(O)CH₃. In embodiments, R² is independently—NHC(O)CH₂CH₃. In embodiments, R² is independently —NHC(O)CH(CH₃)₂. Inembodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein. In embodiments, R² is independently—C(O)OCH₃. In embodiments, R² is independently —C(O)OCH₂CH₃. Inembodiments, R² is independently —C(O)OCH(CH₃)₂. In embodiments, R² isindependently —C(O)OC(CH₃)₃. In embodiments, R² is independently—NHC(O)CH₃. In embodiments, R² is independently —NHC(O)CH₂CH₃. Inembodiments, R² is independently —NHC(O)CH(CH₃)₂. In embodiments, R² isindependently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5), R², z2, and Ring B areas described herein.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R^(1.2), R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), and R² are as described herein. In embodiments, R²is independently —C(O)OCH₃. In embodiments, R² is independently—C(O)OCH₂CH₃. In embodiments, R² is independently —C(O)OCH(CH₃)₂. Inembodiments, R² is independently —C(O)OC(CH₃)₃. In embodiments, R² isindependently —NHC(O)CH₃. In embodiments, R² is independently—NHC(O)CH₂CH₃. In embodiments, R² is independently —NHC(O)CH(CH₃)₂. Inembodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

and R^(1.2) and R^(1.3) are as described herein.

In embodiments, the compound has the formula:

and R^(1.2) and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.2) and R² are as described herein. In embodiments, R² isindependently —C(O)OCH₃. In embodiments, R² is independently—C(O)OCH₂CH₃. In embodiments, R² is independently —C(O)OCH(CH₃)₂. Inembodiments, R² is independently-C(O)OC(CH₃)₃. In embodiments, R² isindependently-NHC(O)CH₃. In embodiments, R² is independently—NHC(O)CH₂CH₃. In embodiments, R² is independently —NHC(O)CH(CH₃)₂. Inembodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

and R^(1.2) is as described herein.

In embodiments, the compound has the formula:

and R¹, R², z1, z2, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R¹, R², z1, and Ring A are as described herein. In embodiments, R²is independently —C(O)OCH₃. In embodiments, R² is independently—C(O)OCH₂CH₃. In embodiments, R² is independently —C(O)OCH(CH₃)₂. Inembodiments, R² is independently —C(O)OC(CH₃)₃. In embodiments, R² isindependently —NHC(O)CH₃. In embodiments, R² isindependently-NHC(O)CH₂CH₃. In embodiments, R² is independently—NHC(O)CH(CH₃)₂. In embodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

and R¹, R², z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R¹, z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R^(2.1), R^(2.2), R^(2.3), R^(2.4), R^(2.5), R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are as described herein.

In embodiments, the compound has the formula:

and R^(2.1), R^(2.2), R^(2.3), R^(2.4), R^(2.5), R¹, z1, and Ring A areas described herein.

In embodiments, the compound has the formula:

and R^(2.3), R¹, z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R^(2.2), R¹, z1, and Ring A are as described herein.

In embodiments, the compound has the formula:

and R^(2.2), R^(2.3), R^(2.4), R¹, z1, and Ring A are as describedherein.

In embodiments, the compound has the formula:

and R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R² is as described herein.

In embodiments, the compound has the formula:

and R² is as described herein. In embodiments, R² is independently—C(O)OCH₃. In embodiments, R² is independently —C(O)OCH₂CH₃. Inembodiments, R² is independently —C(O)OCH(CH₃)₂. In embodiments, R² isindependently —C(O)OC(CH₃)₃. In embodiments, R² is independently—NHC(O)CH₃. In embodiments, R² is independently —NHC(O)CH₂CH₃. Inembodiments, R² is independently —NHC(O)CH(CH₃)₂. In embodiments, R² isindependently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

and R^(1.3), R², z2, and Ring B are as described herein.

In embodiments, the compound has the formula:

and R^(1.3) and R² are as described herein.

In embodiments, the compound has the formula:

and R^(1.3) and R² are as described herein. In embodiments, R² isindependently —C(O)OCH₃. In embodiments, R² is independently—C(O)OCH₂CH₃. In embodiments, R² is independently —C(O)OCH(CH₃)₂. Inembodiments, R² is independently-C(O)OC(CH₃)₃. In embodiments, R² isindependently-NHC(O)CH₃. In embodiments, R² is independently—NHC(O)CH₂CH₃. In embodiments, R² is independently —NHC(O)CH(CH₃)₂. Inembodiments, R² is independently —NHC(O)C(CH₃)₃.

In embodiments, the compound has the formula:

and R^(1.3) is as described herein.

In embodiments, Ring A is aryl (e.g. C₆-C₁₂ aryl, C₆-C₁₀ aryl, or C₆aryl). In embodiments, Ring A is C₆-C₁₂ aryl. In embodiments, Ring A isC₆-C₁₀ aryl. In embodiments, Ring A is C₆ aryl. It will be understoodwhen z1 is 0, Ring A is unsubstituted (e.g., unsubstituted aryl orunsubstituted heteroaryl) in addition to the bond to L (e.g., bond or—N(R⁵)—). It will be understood when z1 is greater than 0 (e.g., 1, 2,3, or 4), Ring A is substituted with one or more R¹ substituents (e.g.,R′-substituted aryl or R¹-substituted heteroaryl) in addition to thebond to L (e.g., bond or —N(R⁵)—).

In embodiments, Ring A is heteroaryl (e.g. 5 to 12 membered heteroaryl,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, Ring A is 5 to 12 memberedheteroaryl. In embodiments, Ring A is 5 to 10 membered heteroaryl. Inembodiments, Ring A is 5 to 9 membered heteroaryl. In embodiments, RingA is 5 to 6 membered heteroaryl.

In embodiments, Ring A is naphthyl. In embodiments, Ring A is biphenyl.In embodiments, Ring A is phenyl. In embodiments, Ring A is pyridyl. Inembodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl.In embodiments, Ring A is oxazolyl. In embodiments, Ring A isisoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring Ais furanyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring Ais thienyl. In embodiments, Ring A is 2-pyridyl. In embodiments, Ring Ais 3-pyridyl. In embodiments, Ring A is 4-pyridyl.

In embodiments, Ring A is indolinyl. In embodiments, Ring A isindazolyl. In embodiments, Ring A is benzimidazolyl. In embodiments,Ring A is benzoxazolyl. In embodiments, Ring A is azaindolyl. Inembodiments, Ring A is purinyl. In embodiments, Ring A is indolyl. Inembodiments, Ring A is pyrazinyl. In embodiments, Ring A is pyrrolyl. Inembodiments, Ring A is imidazolyl. In embodiments, Ring A is pyrazolyl.In embodiments, Ring A is triazolyl. In embodiments, Ring A istetrazolyl.

In embodiments, Ring A is a phenyl or 5 to 6 membered heteroaryl. Inembodiments, Ring A is a phenyl.

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. Two adjacent R¹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R¹ is independently halogen. In embodiments, R¹ isindependently unsubstituted methyl. In embodiments, R¹ is independentlyunsubstituted ethyl. In embodiments, R¹ is independently unsubstitutedpropyl. In embodiments, R¹ is independently unsubstituted isopropyl. Inembodiments, R¹ is independently unsubstituted n-propyl. In embodiments,R¹ is independently unsubstituted butyl. In embodiments, R¹ isindependently unsubstituted n-butyl. In embodiments, R¹ is independentlyunsubstituted t-butyl. In embodiments, R¹ is independently unsubstitutediso-butyl. In embodiments, R¹ is independently unsubstituted C₁-C₈alkyl. In embodiments, R¹ is independently halo-substituted methyl. Inembodiments, R¹ is independently halo-substituted ethyl. In embodiments,R¹ is independently halo-substituted isopropyl. In embodiments, R¹ isindependently halo-substituted n-propyl. In embodiments, R¹ isindependently halo-substituted n-butyl. In embodiments, R¹ isindependently halo-substituted t-butyl. In embodiments, R¹ isindependently halo-substituted C₁-C₈ alkyl.

In embodiments, R¹ is independently —CX¹ ₃. In embodiments, R¹ isindependently —CHX¹ ₂. In embodiments, R¹ is independently-CH₂X¹. Inembodiments, R¹ is independently —OCX¹ ₃. In embodiments, R¹ isindependently —OCH₂X¹. In embodiments, R¹ is independently —OCHX¹ ₂. Inembodiments, R¹ is independently —CN. In embodiments, R¹ isindependently —SO_(n1)R^(1D). In embodiments, R¹ is independently—SR^(1D). In embodiments, R¹ is independently —SO_(v1)NR^(1A)R^(1B). Inembodiments, R¹ is independently —NHC(O)NR^(1A)R^(1B). In embodiments,R¹ is independently-N(O)_(m1). In embodiments, R¹ isindependently-NR^(1A)R^(1B). In embodiments, R¹ is independently—C(O)R^(1C). In embodiments, R¹ is independently —C(O)—OR^(1C). Inembodiments, R¹ is independently —C(O)NR^(1A)R^(1B). In embodiments, R¹is independently —OR^(1D). In embodiments, R¹ is independently—NR^(1A)SO₂R^(1D). In embodiments, R¹ is independently—NR^(1A)C(O)R^(1C). In embodiments, R¹ is independently—NR^(1A)C(O)OR^(1C). In embodiments, R¹ is independently—NR^(1A)OR^(1C). In embodiments, R¹ is independently —OH. Inembodiments, R¹ is independently —NH₂. In embodiments, R¹ isindependently —COOH. In embodiments, R¹ is independently —CONH₂. Inembodiments, R¹ is independently —NO₂. In embodiments, R¹ isindependently —SH. In embodiments, R¹ is independently halogen. Inembodiments, R¹ is independently —F. In embodiments, R¹ is independently—Cl. In embodiments, R¹ is independently-Br. In embodiments, R¹ isindependently —I. In embodiments, R¹ is independently —CF₃. Inembodiments, R¹ is independently —CHF₂. In embodiments, R¹ isindependently —CH₂F. In embodiments, R¹ is independently —OCF₃. Inembodiments, R¹ is independently —OCH₂F. In embodiments, R¹ isindependently —OCHF₂. In embodiments, R¹ is independently —OCH₃. Inembodiments, R¹ is independently —OCH₂CH₃. In embodiments, R¹ isindependently —OCH₂CH₂CH₃. In embodiments, R¹ is independently—OCH(CH₃)₂. In embodiments, R¹ is independently —OC(CH₃)₃. Inembodiments, R¹ is independently —SCH₃. In embodiments, R¹ isindependently —SCH₂CH₃. In embodiments, R¹ is independently —SCH₂CH₂CH₃.In embodiments, R¹ is independently —SCH(CH₃)₂. In embodiments, R¹ isindependently —SC(CH₃)₃. In embodiments, R¹ is independently —CH₃. Inembodiments, R¹ is independently —CH₂CH₃. In embodiments, R¹ isindependently —CH₂CH₂CH₃. In embodiments, R¹ is independently —CH(CH₃)₂.In embodiments, R¹ is independently —C(CH₃)₃. In embodiments, R¹ isindependently —CH₂CH₂C(O)OCH₃. In embodiments, R¹ is independently—CH₂CH(CH₃)C(O)OCH₃. In embodiments, R¹ is independently —N₃.

In embodiments, R^(1.1) is independently hydrogen. In embodiments,R^(1.1) is independently —CX¹ ₃. In embodiments, R^(1.1) isindependently —CHX¹ ₂. In embodiments, R^(1.1) is independently —CH₂X¹.In embodiments, R^(1.1) is independently —OCX¹ ₃. In embodiments,R^(1.1) is independently —OCH₂X¹. In embodiments, R^(1.1) isindependently —OCHX¹ ₂. In embodiments, R^(1.1) is independently —CN. Inembodiments, R^(1.1) is independently —SO_(n1)R^(1D). In embodiments,R^(1.1) is independently —SO_(v1)NR^(1A)R^(1B). In embodiments, R^(1.1)is independently —NHC(O)NR^(1A)R^(1B). In embodiments, R^(1.1) isindependently —N(O)_(m1). In embodiments, R^(1.1) is independently—NR^(1A)R^(1B). In embodiments, R^(1.1) is independently —C(O)R^(1C). Inembodiments, R^(1.1) is independently —C(O)OR^(1C). In embodiments,R^(1.1) is independently —C(O)NR^(1A)R^(1B). In embodiments, R^(1.1) isindependently —OR^(1D). In embodiments, R^(1.1) is independently—NR^(1A)SO₂R^(1D). In embodiments, R^(1.1) is independently—NR^(1A)C(O)R^(1C). In embodiments, R^(1.1) is independently—NR^(1A)C(O)OR^(1C). In embodiments, R^(1.1) is independently—NR^(1A)OR^(1C). In embodiments, R^(1.1) is independently —OH. Inembodiments, R^(1.1) is independently —NH₂. In embodiments, R^(1.1) isindependently —COOH. In embodiments, R^(1.1) is independently —CONH₂. Inembodiments, R^(1.1) is independently —NO₂. In embodiments, R^(1.1) isindependently —SH. In embodiments, R^(1.1) is independently halogen. Inembodiments, R^(1.1) is independently —F. In embodiments, R^(1.1) isindependently —Cl. In embodiments, R^(1.1) is independently —Br. Inembodiments, R^(1.1) is independently —I. In embodiments, R^(1.1) isindependently —CF₃. In embodiments, R^(1.1) is independently —CHF₂. Inembodiments, R^(1.1) is independently —CH₂F. In embodiments, R^(1.1) isindependently —OCF₃. In embodiments, R^(1.1) is independently —OCH₂F. Inembodiments, R^(1.1) is independently —OCHF₂. In embodiments, R^(1.1) isindependently —OCH₃. In embodiments, R^(1.1) is independently —OCH₂CH₃.In embodiments, R^(1.1) is independently —OCH₂CH₂CH₃. In embodiments,R^(1.1) is independently —OCH(CH₃)₂. In embodiments, R^(1.1) isindependently —OC(CH₃)₃. In embodiments, R^(1.1) is independently —SCH₃.In embodiments, R^(1.1) is independently —SCH₂CH₃. In embodiments,R^(1.1) is independently —SCH₂CH₂CH₃. In embodiments, R^(1.1) isindependently —SCH(CH₃)₂. In embodiments, R^(1.1) is independently—SC(CH₃)₃. In embodiments, R^(1.1) is independently —CH₃. Inembodiments, R^(1.1) is independently —CH₂CH₃. In embodiments, R^(1.1)is independently —CH₂CH₂CH₃. In embodiments, R^(1.1) is independently—CH(CH₃)₂. In embodiments, R^(1.1) is independently —C(CH₃)₃. Inembodiments, R^(1.1) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(1.1) is independently-CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(U) isindependently-N₃. In embodiments, R^(1.1) is independently —SR^(1D).

In embodiments, R^(1.2) is independently hydrogen. In embodiments,R^(1.2) is independently —CX¹ ₃. In embodiments, R^(1.2) isindependently —CHX¹ ₂. In embodiments, R^(1.2) is independently —CH₂X¹.In embodiments, R^(1.2) is independently —OCX¹ ₃. In embodiments,R^(1.2) is independently-OCH₂X¹. In embodiments, R^(1.2) isindependently-OCHX¹ ₂. In embodiments, R^(1.2) is independently —CN. Inembodiments, R^(1.2) is independently —SO_(n1)R^(1D). In embodiments,R^(1.2) is independently —SO_(v1)NR^(1A)R^(1B). In embodiments, R^(1.2)is independently —NHC(O)NR^(1A)R^(1B). In embodiments, R^(1.2) isindependently —N(O)_(m1). In embodiments, R^(1.2) is independently—NR^(1A)R^(1B). In embodiments, R^(1.2) is independently —C(O)R^(1C). Inembodiments, R^(1.2) is independently-C(O)OR^(1C). In embodiments,R^(1.2) is independently-C(O)NR^(1A)R^(1B). In embodiments, R^(1.2) isindependently —OR^(1D). In embodiments, R^(1.2) is independently—NR^(1A)SO₂R^(1D). In embodiments, R^(1.2) is independently—NR^(1A)C(O)R^(1C). In embodiments, R^(1.2) is independently—NR^(1A)C(O)OR^(1C). In embodiments, R^(1.2) is independently—NR^(1A)OR^(1C). In embodiments, R^(1.2) is independently —OH. Inembodiments, R^(1.2) is independently —NH₂. In embodiments, R^(1.2) isindependently —COOH. In embodiments, R^(1.2) is independently —CONH₂. Inembodiments, R^(1.2) is independently —NO₂. In embodiments, R^(1.2) isindependently —SH. In embodiments, R^(1.2) is independently halogen. Inembodiments, R^(1.2) is independently —F. In embodiments, R^(1.2) isindependently —Cl. In embodiments, R^(1.2) is independently —Br. Inembodiments, R^(1.2) is independently —I. In embodiments, R^(1.2) isindependently —CF₃. In embodiments, R^(1.2) is independently —CHF₂. Inembodiments, R^(1.2) is independently —CH₂F. In embodiments, R^(1.2) isindependently —OCF₃. In embodiments, R^(1.2) is independently —OCH₂F. Inembodiments, R^(1.2) is independently —OCHF₂. In embodiments, R^(1.2) isindependently —OCH₃. In embodiments, R^(1.2) is independently —OCH₂CH₃.In embodiments, R^(1.2) is independently —OCH₂CH₂CH₃. In embodiments,R^(1.2) is independently —OCH(CH₃)₂. In embodiments, R^(1.2) isindependently —OC(CH₃)₃. In embodiments, R^(1.2) is independently —SCH₃.In embodiments, R^(1.2) is independently —SCH₂CH₃. In embodiments,R^(1.2) is independently —SCH₂CH₂CH₃. In embodiments, R^(1.2) isindependently —SCH(CH₃)₂. In embodiments, R^(1.2) is independently—SC(CH₃)₃. In embodiments, R^(1.2) is independently —CH₃. Inembodiments, R^(1.2) is independently —CH₂CH₃. In embodiments, R^(1.2)is independently —CH₂CH₂CH₃. In embodiments, R^(1.2) is independently—CH(CH₃)₂. In embodiments, R^(1.2) is independently —C(CH₃)₃. Inembodiments, R^(1.2) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(1.2) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(1.2) isindependently —N₃. In embodiments, R^(1.2) is independently —SR^(1D).

In embodiments, R^(1.3) is independently hydrogen. In embodiments,R^(1.3) is independently —CX¹ ₃. In embodiments, R^(1.3) isindependently-CHX¹ ₂. In embodiments, R^(1.3) is independently —CH₂X¹.In embodiments, R^(1.3) is independently —OCX¹ ₃. In embodiments,R^(1.3) is independently —OCH₂X¹. In embodiments, R^(1.3) isindependently —OCHX^(1D). In embodiments, R^(1.3) is independently —CN.In embodiments, R^(1.3) is independently —SO_(n1)R^(1D). In embodiments,R^(1.3) is independently —SO_(v1)NR^(1A)R^(1B). In embodiments, R^(1.3)is independently —NHC(O)NR^(1A)R^(1B). In embodiments, R^(1.3) isindependently —N(O)_(m1). In embodiments, R^(1.3) is independently—NR^(1A)R^(1B). In embodiments, R^(1.3) is independently —C(O)R^(1C). Inembodiments, R^(1.3) is independently —C(O)OR^(1C). In embodiments,R^(1.3) is independently —C(O)NR^(1A)R^(1B). In embodiments, R^(1.3) isindependently —OR^(1D). In embodiments, R^(1.3) is independently—NR^(1A)SO₂R^(1D). In embodiments, R^(1.3) is independently—NR^(1A)C(O)R^(1C). In embodiments, R^(1.3) is independently—NR^(1A)C(O)OR^(1C). In embodiments, R^(1.3) is independently—NR^(1A)OR^(1C). In embodiments, R^(1.3) is independently —OH. Inembodiments, R^(1.3) is independently —NH₂. In embodiments, R^(1.3) isindependently —COOH. In embodiments, R^(1.3) is independently —CONH₂. Inembodiments, R^(1.3) is independently —NO₂. In embodiments, R^(1.3) isindependently —SH. In embodiments, R^(1.3) is independently halogen. Inembodiments, R^(1.3) is independently-F. In embodiments, R^(1.3) isindependently-Cl. In embodiments, R^(1.3) is independently —Br. Inembodiments, R^(1.3) is independently —I. In embodiments, R^(1.3) isindependently —CF₃. In embodiments, R^(1.3) is independently —CHF₂. Inembodiments, R^(1.3) is independently —CH₂F. In embodiments, R^(1.3) isindependently —OCF₃. In embodiments, R^(1.3) is independently —OCH₂F. Inembodiments, R^(1.3) is independently —OCHF₂. In embodiments, R^(1.3) isindependently —OCH₃. In embodiments, R^(1.3) is independently —OCH₂CH₃.In embodiments, R^(1.3) is independently —OCH₂CH₂CH₃. In embodiments,R^(1.3) is independently —OCH(CH₃)₂. In embodiments, R^(1.3) isindependently —OC(CH₃)₃. In embodiments, R^(1.3) is independently —SCH₃.In embodiments, R^(1.3) is independently —SCH₂CH₃. In embodiments,R^(1.3) is independently —SCH₂CH₂CH₃. In embodiments, R^(1.3) isindependently —SCH(CH₃)₂. In embodiments, R^(1.3) isindependently-SC(CH₃)₃. In embodiments, R^(1.3) is independently-CH₃. Inembodiments, R^(1.3) is independently —CH₂CH₃. In embodiments, R^(1.3)is independently —CH₂CH₂CH₃. In embodiments, R^(1.3) is independently—CH(CH₃)₂. In embodiments, R^(1.3) is independently —C(CH₃)₃. Inembodiments, R^(1.3) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(1.3) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(1.3) isindependently —N₃. In embodiments, R^(1.3) is independently —SR^(1D).

In embodiments, R^(1.4) is independently hydrogen. In embodiments,R^(1.4) is independently —CX¹ ₃. In embodiments, R^(1.4) isindependently —CHX¹ ₂. In embodiments, R^(1.4) is independently —CH₂X¹.In embodiments, R^(1.4) is independently —OCX¹ ₃. In embodiments,R^(1.4) is independently —OCH₂X¹. In embodiments, R^(1.4) isindependently —OCHX¹ ₂. In embodiments, R^(1.4) is independently —CN. Inembodiments, R^(1.4) is independently —SO_(n1)R^(1D). In embodiments,R^(1.4) is independently —SO_(v1)NR^(1A)R^(1B). In embodiments, R^(1.4)is independently —NHC(O)NR^(1A)R^(1B). In embodiments, R^(1.4) isindependently —N(O)_(m1). In embodiments, R^(1.4) is independently—NR^(1A)R^(1B). In embodiments, R^(1.4) is independently —C(O)R^(1C). Inembodiments, R^(1.4) is independently —C(O)OR^(1C). In embodiments,R^(1.4) is independently —C(O)NR^(1A)R^(1B). In embodiments, R^(1.4) isindependently-OR^(1D). In embodiments, R^(1.4) is independently—NR^(1A)SO₂R^(1D). In embodiments, R^(1.4) is independently—NR^(1A)C(O)R^(1C). In embodiments, R^(1.4) is independently—NR^(1A)C(O)OR^(1C). In embodiments, R^(1.4) is independently—NR^(1A)OR^(1C). In embodiments, R^(1.4) is independently —OH. Inembodiments, R^(1.4) is independently —NH₂. In embodiments, R^(1.4) isindependently —COOH. In embodiments, R^(1.4) is independently-CONH₂. Inembodiments, R^(1.4) is independently-NO₂. In embodiments, R^(1.4) isindependently —SH. In embodiments, R^(1.4) is independently halogen. Inembodiments, R^(1.4) is independently —F. In embodiments, R^(1.4) isindependently —Cl. In embodiments, R^(1.4) is independently —Br. Inembodiments, R^(1.4) is independently —I. In embodiments, R^(1.4) isindependently —CF₃. In embodiments, R^(1.4) is independently —CHF₂. Inembodiments, R^(1.4) is independently —CH₂F. In embodiments, R^(1.4) isindependently —OCF₃. In embodiments, R^(1.4) is independently —OCH₂F. Inembodiments, R^(1.4) is independently —OCHF₂. In embodiments, R^(1.4) isindependently —OCH₃. In embodiments, R^(1.4) is independently —OCH₂CH₃.In embodiments, R^(1.4) is independently —OCH₂CH₂CH₃. In embodiments,R^(1.4) is independently —OCH(CH₃)₂. In embodiments, R^(1.4) isindependently —OC(CH₃)₃. In embodiments, R^(1.4) is independently —SCH₃.In embodiments, R^(1.4) is independently —SCH₂CH₃. In embodiments,R^(1.4) is independently —SCH₂CH₂CH₃. In embodiments, R^(1.4) isindependently —SCH(CH₃)₂. In embodiments, R^(1.4) is independently—SC(CH₃)₃. In embodiments, R^(1.4) is independently —CH₃. Inembodiments, R^(1.4) is independently —CH₂CH₃. In embodiments, R^(1.4)is independently —CH₂CH₂CH₃. In embodiments, R^(1.4) is independently—CH(CH₃)₂. In embodiments, R^(1.4) is independently —C(CH₃)₃. Inembodiments, R^(1.4) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(1.4) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(1.4) isindependently —N₃. In embodiments, R^(1.4) is independently —SR^(1D).

In embodiments, R^(1.5) is independently hydrogen. In embodiments,R^(1.5) is independently —CX¹ ₃. In embodiments, R^(1.5) isindependently —CHX¹ ₂. In embodiments, R^(1.5) is independently-CH₂X¹.In embodiments, R^(1.5) is independently-OCX¹ ₃. In embodiments, R^(1.5)is independently —OCH₂X¹. In embodiments, R^(1.5) is independently—OCHX¹ ₂. In embodiments, R^(1.5) is independently —CN. In embodiments,R^(1.5) is independently —SO_(n1)R^(1D). In embodiments, R^(1.5) isindependently —SO_(v1)NR^(1A)R^(1B). In embodiments, R^(1.5) isindependently —NHC(O)NR^(1A)R^(1B). In embodiments, R^(1.5) isindependently —N(O)_(m1). In embodiments, R^(1.5) is independently—NR^(1A)R^(1B). In embodiments, R^(1.5) is independently —C(O)R^(1C). Inembodiments, R^(1.5) is independently —C(O)OR^(1C). In embodiments,R^(1.5) is independently —C(O)NR^(1A)R^(1B). In embodiments, R^(1.5) isindependently —OR^(1D). In embodiments, R^(1.5) is independently—NR^(1A)SO₂R^(1D). In embodiments, R^(1.5) is independently—NR^(1A)C(O)R^(1C). In embodiments, R^(1.5) is independently—NR^(1A)C(O)OR^(1C). In embodiments, R^(1.5) isindependently-NR^(1A)OR^(1C). In embodiments, R^(1.5) isindependently-OH. In embodiments, R^(1.5) is independently —NH₂. Inembodiments, R^(1.5) is independently —COOH. In embodiments, R^(1.5) isindependently —CONH₂. In embodiments, R^(1.5) is independently —NO₂. Inembodiments, R^(1.5) is independently —SH. In embodiments, R^(1.5) isindependently halogen. In embodiments, R^(1.5) is independently —F. Inembodiments, R^(1.5) is independently —Cl. In embodiments, R^(1.5) isindependently —Br. In embodiments, R^(1.5) is independently —I. Inembodiments, R^(1.5) is independently —CF₃. In embodiments, R^(1.5) isindependently —CHF₂. In embodiments, R^(1.5) is independently —CH₂F. Inembodiments, R^(1.5) is independently —OCF₃. In embodiments, R^(1.5) isindependently —OCH₂F. In embodiments, R^(1.5) is independently —OCHF₂.In embodiments, R^(1.5) is independently —OCH₃. In embodiments, R^(1.5)is independently —OCH₂CH₃. In embodiments, R^(1.5) is independently—OCH₂CH₂CH₃. In embodiments, R^(1.5) is independently —OCH(CH₃)₂. Inembodiments, R^(1.5) is independently —OC(CH₃)₃. In embodiments, R^(1.5)is independently —SCH₃. In embodiments, R^(1.5) is independently—SCH₂CH₃. In embodiments, R^(1.5) is independently —SCH₂CH₂CH₃. Inembodiments, R^(1.5) is independently —SCH(CH₃)₂. In embodiments,R^(1.5) is independently —SC(CH₃)₃. In embodiments, R^(1.5) isindependently —CH₃. In embodiments, R^(1.5) is independently-CH₂CH₃. Inembodiments, R^(1.5) is independently-CH₂CH₂CH₃. In embodiments, R^(1.5)is independently —CH(CH₃)₂. In embodiments, R^(1.5) is independently—C(CH₃)₃. In embodiments, R^(1.5) is independently —CH₂CH₂C(O)OCH₃. Inembodiments, R^(1.5) is independently —CH₂CH(CH₃)C(O)OCH₃. Inembodiments, R^(1.5) is independently —N₃. In embodiments, R^(1.5) isindependently —SR^(1D).

In embodiments, R¹ is independently hydrogen, halogen, —CX¹ ₃, —CHX¹ ₃,—CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —SO_(n1)R^(1D),—SO_(v1)NR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B),—C(O)R^(1C), —C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D),—NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),—NR^(1A)OR^(1C), substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R¹ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R¹ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R¹ is independentlyunsubstituted methyl. In embodiments, R¹ is independently unsubstitutedethyl. In embodiments, R¹ is independently unsubstituted propyl. Inembodiments, R¹ is independently unsubstituted isopropyl. Inembodiments, R¹ is independently unsubstituted tert-butyl. Inembodiments, R¹ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R¹ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R¹ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R¹ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R¹ isindependently substituted cycloalkyl (e.g., C₃-C₅, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R¹ is independently unsubstituted cycloalkyl(e.g., C₃-C₅, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R¹ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R¹ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R¹ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R¹ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R¹ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R¹is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R¹ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R¹ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R¹ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R¹ is independently

halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R¹ is independentlyhalogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X¹ is independently —F, —Cl, —Br, or—I.

In embodiments, two adjacent R¹ substituents may be joined to form asubstituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R¹ substituents may be joined to form asubstituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, two adjacent R¹ substituents may be joined toform a substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, two adjacent R¹ substituents may be joined to form anunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, two adjacent R¹ substituents may be joined to form asubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, two adjacent R¹ substituents may be joined to form asubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4to 6 membered, 4 to 5 membered, or 5 to 6 membered In embodiments, twoadjacent R¹ substituents may be joined to form an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, twoadjacent R¹ substituents may be joined to form a substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,two adjacent R¹ substituents may be joined to form a substituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, two adjacent R¹substituents may be joined to form an unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, two adjacent R¹ substituents may bejoined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, two adjacent R¹ substituents may be joined to form asubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, two adjacent R¹substituents may be joined to form an unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R¹ substituents may be joined to form anR²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), R²⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R²⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R²⁰-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, two adjacent R¹ substituents may be joined to form anunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(1.1) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.1) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1.1) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.1) is independentlyunsubstituted methyl. In embodiments, R^(1.1) is independentlyunsubstituted ethyl. In embodiments, R^(1.1) is independentlyunsubstituted propyl. In embodiments, R^(1.1) is independentlyunsubstituted isopropyl. In embodiments, R^(1.1) is independentlyunsubstituted tert-butyl. In embodiments, R^(1.1) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1.1) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(1.1) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1.1) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.1) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1.1) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.1) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1.1) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(1.1) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(1.1) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1.1) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(1.1) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(1.1) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.1) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(1.1)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(1.1) is independently hydrogen,

halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(1.1) isindependently hydrogen,halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X¹ is independently —F, —Cl, —Br, or—I.

In embodiments, R^(1.2) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.2) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1.2) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.2) is independentlyunsubstituted methyl. In embodiments, R^(1.2) is independentlyunsubstituted ethyl. In embodiments, R^(1.2) is independentlyunsubstituted propyl. In embodiments, R^(1.2) is independentlyunsubstituted isopropyl. In embodiments, R^(1.2) is independentlyunsubstituted tert-butyl. In embodiments, R^(1.2) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1.2) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(1.2) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1.2) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.2) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1.2) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.2) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1.2) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(1.2) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(1.2) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1.2) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(1.2) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(1.2) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.2) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(1.2)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(1.2) is independently hydrogen,

halogen, —CX³ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(1.2) isindependently hydrogen,halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X¹ is independently —F, —Cl, —Br, or—I.

In embodiments, R^(1.3) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.3) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1.3) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.3) is independentlyunsubstituted methyl. In embodiments, R^(1.3) is independentlyunsubstituted ethyl. In embodiments, R^(1.3) is independentlyunsubstituted propyl. In embodiments, R^(1.3) is independentlyunsubstituted isopropyl. In embodiments, R^(1.3) is independentlyunsubstituted tert-butyl. In embodiments, R^(1.3) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1.3) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(1.3) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1.3) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.3) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1.3) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.3) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1.3) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(1.3) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(1.3) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1.3) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(1.3) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(1.3) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.3) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(1.3)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(1.3) is independently hydrogen,

halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(1.3) isindependently hydrogen,halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁—C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X¹ is independently —F, —Cl, —Br, or—I.

In embodiments, R^(1.4) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.4) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1.4) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.4) is independentlyunsubstituted methyl. In embodiments, R^(1.4) is independentlyunsubstituted ethyl. In embodiments, R^(1.4) is independentlyunsubstituted propyl. In embodiments, R^(1.4) is independentlyunsubstituted isopropyl. In embodiments, R^(1.4) is independentlyunsubstituted tert-butyl. In embodiments, R^(1.4) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1.4) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(1.4) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1.4) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.4) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1.4) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.4) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1.4) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(1.4) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(1.4) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1.4) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(1.4) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(1.4) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.4) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(1.4)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(1.4) is independently hydrogen, halogen, —CX⁴ ₃,—CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R²⁰-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), R²⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R²⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R²⁰-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R^(1.4) is independently hydrogen,

halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X¹ is independently —F, —Cl, —Br, or—I.

In embodiments, R^(1.5) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.5) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1.5) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1.5) is independentlyunsubstituted methyl. In embodiments, R^(1.5) is independentlyunsubstituted ethyl. In embodiments, R^(1.5) is independentlyunsubstituted propyl. In embodiments, R^(1.5) is independentlyunsubstituted isopropyl. In embodiments, R^(1.5) is independentlyunsubstituted tert-butyl. In embodiments, R^(1.5) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1.5) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(1.5) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1.5) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.5) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1.5) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1.5) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1.5) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(1.5) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(1.5) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1.5) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(1.5) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(1.5) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.5) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(1.5)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(1.5) is independently hydrogen,

halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(1.5) isindependently hydrogen,halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁—C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X¹ is independently —F, —Cl, —Br, or—I.

R²⁰ is independently oxo,

halogen, —CX²⁰ ₃, —CHX²⁰ ₂, —CH₂X²⁰, —OCX²⁰ ₃, —OCH₂X²⁰, —OCHX²⁰ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R^(2.1)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R^(2.1)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), R^(2.1)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(2.1)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R^(2.1)-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or R^(2.1)-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R²⁰ is independently oxo,halogen, —CX²⁰ ₃, —CHX²⁰ ₂, —CH₂X²⁰, —OCX²⁰ ₃, —OCH₂X²⁰, —OCHX²⁰ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁰ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁰ isindependently unsubstituted methyl. In embodiments, R²⁰ is independentlyunsubstituted ethyl.

R²¹ is independently oxo,

halogen, —CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹, —OCX²¹ ₃, —OCH₂X²¹, —OCHX²¹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R²²-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R²²-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R²²-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²²-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²²-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²²-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²¹ is independentlyoxo,halogen, —CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹, —OCX²¹ ₃, —OCH₂X²¹, —OCHX²¹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²¹ is independently —F, —Cl, —Br, or —I. In embodiments, R²¹ isindependently unsubstituted methyl. In embodiments, R²¹ is independentlyunsubstituted ethyl.

R²² is independently oxo,

halogen, —CX²² ₃, —CHX²² ₂, —CH₂X²², —OCX²² ₃, —OCH₂X²², —OCHX²² ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²² is independently —F, —Cl, —Br, or —I. In embodiments, R²² isindependently unsubstituted methyl. In embodiments, R²² is independentlyunsubstituted ethyl.

In embodiments, R^(1A) is independently hydrogen. In embodiments, R^(1A)is independently —CX^(1A) ₃. In embodiments, R^(1A) is independently—CHX^(1A) ₂. In embodiments, R^(1A) is independently —CH₂X^(1A). Inembodiments, R^(1A) is independently —CN. In embodiments, R^(1A) isindependently —COOH. In embodiments, R^(1A) is independently —CONH₂. Inembodiments, X^(1A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(1A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1A) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1A) is independentlyunsubstituted methyl. In embodiments, R^(1A) is independentlyunsubstituted ethyl. In embodiments, R^(1A) is independentlyunsubstituted propyl. In embodiments, R^(1A) is independentlyunsubstituted isopropyl. In embodiments, R^(1A) is independentlyunsubstituted tert-butyl. In embodiments, R^(1A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(1A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(1A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(1A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(1A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1A) is independently hydrogen, —CX^(1A) ₃, —CHX^(1A)₂, —CH₂X^(1A), —CN, —COOH, —CONH₂, R^(20A)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(20A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(20A)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(20A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(20A)-substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl), or R^(20A)-substituted or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, R^(1A) is independently hydrogen, —CX^(1A) ₃,—CHX^(1A) ₂, —CH₂X^(1A), —CN, —COOH, —CONH₂, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(1A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(1A) is independently hydrogen. In embodiments, R^(1A) isindependently unsubstituted methyl. In embodiments, R^(1A) isindependently unsubstituted ethyl.

In embodiments, R^(1A) and R^(1B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(20A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(20A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(20A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(20A) is independently oxo,

halogen, —CX^(20A) ₃, —CHX^(20A) ₂, —CH₂X^(20A), —OCX^(20A) ₃,—OCH₂X^(20A), —OCHX^(20A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(21A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(21A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(21A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(21A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(21A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(21A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(20A) isindependently oxo,halogen, —CX^(20A) ₃, —CHX^(20A) ₂, —CH₂X^(20A), —OCX^(20A) ₃,—OCH₂X^(20A), —OCHX^(20A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(20A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(20A) is independently unsubstituted methyl. Inembodiments, R^(20A) is independently unsubstituted ethyl.

R^(21A) is independently oxo,

halogen, —CX^(21A) ₃, —CHX^(21A) ₂, —CH₂X^(21A), —OCX^(21A) ₃,—OCH₂X^(21A), —OCHX^(21A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(22A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(22A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(22A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(22A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(22A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(22A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(21A) isindependently oxo,halogen, —CX^(21A) ₃, —CHX^(21A) ₂, —CH₂X^(21A), —OCX^(21A) ₃,—OCH₂X^(21A), —OCHX^(21A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁—C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(21A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(21A) is independently unsubstituted methyl. Inembodiments, R^(21A) is independently unsubstituted ethyl.

R^(22A) is independently oxo,

halogen, —CX^(22A) ₃, —CHX^(22A) ₂, —CH₂X^(22A), —OCX^(22A) ₃,—OCH₂X^(22A), —OCHX^(22A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(22A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(22A) is independently unsubstituted methyl. Inembodiments, R^(22A) is independently unsubstituted ethyl.

In embodiments, R^(1B) is independently hydrogen. In embodiments, R^(1B)is independently —CX^(1B) ₃. In embodiments, R^(1B) is independently—CHX^(1B) ₂. In embodiments, R^(1B) is independently —CH₂X^(1B). Inembodiments, R^(1B) is independently —CN. In embodiments, R^(1B) isindependently —COOH. In embodiments, R^(1B) is independently —CONH₂. Inembodiments, X^(1B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(1B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1B) is independentlyunsubstituted methyl. In embodiments, R^(1B) is independentlyunsubstituted ethyl. In embodiments, R^(1B) is independentlyunsubstituted propyl. In embodiments, R^(1B) is independentlyunsubstituted isopropyl. In embodiments, R^(1B) is independentlyunsubstituted tert-butyl. In embodiments, R^(1B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(1B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(1B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(1B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(1B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1A) and R^(1B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1A) and R^(1B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(1A) and R^(1B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1A) and R^(1B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1A) and R^(1B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(1B) is independently

hydrogen, —CX^(1B) ₃, —CHX^(1B) ₂, —CH₂X^(1B), —CN, —COOH, —CONH₂,R^(20B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(20B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(20B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(20B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(20B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(20B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1B) is independently hydrogen, —CX^(1B) ₃, —CHX^(1B) ₂, —CH₂X^(1B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(1B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(1B) is independently hydrogen. In embodiments, R^(1B) isindependently unsubstituted methyl. In embodiments, R^(1B) isindependently unsubstituted ethyl.

In embodiments, R^(1A) and R^(1B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(20B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(20B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(20B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(20B) is independently oxo,

halogen, —CX^(20B) ₃, —CHX^(20B) ₂, —CH₂X^(20B), —OCX^(20B) ₃,—OCH₂X^(20B), —OCHX^(20B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(21B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(21B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(21B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(21B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(21B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(21B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(20B) isindependently oxo,halogen, —CX^(20B) ₃, —CHX^(20B) ₂, —CH₂X^(20B), —OCX^(20B) ₃,—OCH₂X^(20B), —OCHX^(20B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(20B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(20B) is independently unsubstituted methyl. Inembodiments, R^(20B) is independently unsubstituted ethyl.

R^(21B) is independently oxo,

halogen, —CX^(21B) ₃, —CHX^(21B) ₂, —CH₂X^(21B), —OCX^(21B) ₃,—OCH₂X^(21B), —OCHX^(21B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(22B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(22B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(22B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(22B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(22B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(22B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(21B) isindependently oxo,halogen, —CX²¹—CHX^(21B) ₂, —CH₂X^(21B), —OCX^(21B) ₃, —OCH₂X^(21B),—OCHX^(21B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(21B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(21B) is independently unsubstituted methyl. In embodiments, R^(21B)is independently unsubstituted ethyl.

R^(22B) is independently oxo,

halogen, —CX^(22B) ₃, —CHX^(22B) ₂, —CH₂X^(22B), —OCX^(22B) ₃,—OCH₂X^(22B), —OCHX^(22B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(22B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(22B) is independently unsubstituted methyl. Inembodiments, R^(22B) is independently unsubstituted ethyl.

In embodiments, R^(1C) is independently hydrogen. In embodiments, R^(1C)is independently —CX^(1C) ₃. In embodiments, R^(1C) is independently—CHX^(1C) ₂. In embodiments, R^(1C) is independently —CH₂X^(1C). Inembodiments, R^(1C) is independently —CN. In embodiments, R^(1C) isindependently —COOH. In embodiments, R^(1C) is independently —CONH₂. Inembodiments, X^(1C) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(1C) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1C) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1C) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1C) is independentlyunsubstituted methyl. In embodiments, R^(1C) is independentlyunsubstituted ethyl. In embodiments, R^(1C) is independentlyunsubstituted propyl. In embodiments, R^(1C) is independentlyunsubstituted isopropyl. In embodiments, R^(1C) is independentlyunsubstituted tert-butyl. In embodiments, R^(1C) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1C) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(1C) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1C) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1C) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1C) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1C) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1C) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(1C) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1C)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(1C) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1C) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(1C) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1C) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1C) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1C) is independently

hydrogen, —CX^(1C) ₃, —CHX^(1C) ₂, —CH₂X^(1C), —CN, —COOH, —CONH₂,R^(20C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(20C)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(20C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(20C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(20C)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(20C)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1C) is independently hydrogen, —CX^(1C) ₃, —CHX^(1C) ₂, —CH₂X^(1C),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(1C) is independently —F, —Cl, —Br, or —I. In embodiments,R^(1C) is independently hydrogen. In embodiments, R^(1C) isindependently unsubstituted methyl. In embodiments, R^(1C) isindependently unsubstituted ethyl.

R^(20C) is independently oxo,

halogen, —CX^(20C) ₃, —CHX^(20C) ₂, —CH₂X^(20C), —OCX^(20C) ₃,—OCH₂X^(20C), —OCHX^(20C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(21C)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(21C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(21C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(21C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(21C)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(21C)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(20C) isindependently oxo,halogen, —CX^(20C) ₃, —CHX^(20C) ₂, —CH₂X^(20C), —OCX^(20C) ₃,—OCH₂X^(20C), —OCHX^(20C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(20C) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(20C) is independently unsubstituted methyl. Inembodiments, R^(20C) is independently unsubstituted ethyl.

R^(21C) is independently oxo,

halogen, —CX^(21C) ₃, —CHX^(21C) ₂, —CH₂X^(21C), —OCX^(21C) ₃,—OCH₂X^(21C), —OCHX^(21C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(22C)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(22C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(22C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(22C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(22C)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(22C)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(21C) isindependently oxo,halogen, —CX^(21C) ₃, —CHX^(21C) ₂, —CH₂X^(21C), —OCX^(21C) ₃,—OCH₂X^(21C), —OCHX^(21C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(21C) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(21C) is independently unsubstituted methyl. Inembodiments, R^(21C) is independently unsubstituted ethyl.

R^(22C) is independently oxo,

halogen, —CX^(22C) ₃, —CHX^(22C) ₂, —CH₂X^(22C), —OCX^(22C) ₃,—OCH₂X^(22C), —OCHX^(22C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(22C) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(22C) is independently unsubstituted methyl. Inembodiments, R^(22C) is independently unsubstituted ethyl.

In embodiments, R^(1D) is independently hydrogen. In embodiments, R^(1D)is independently —CX^(1D) ₃. In embodiments, R^(1D) is independently—CHX^(1D) ₂. In embodiments, R^(1D) is independently —CH₂X^(1D). Inembodiments, R^(1D) is independently —CN. In embodiments, R^(1D) isindependently —COOH. In embodiments, R^(1D) is independently —CONH₂. Inembodiments, X^(1D) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(1D) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1D) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(1D) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(1D) is independentlyunsubstituted methyl. In embodiments, R^(1D) is independentlyunsubstituted ethyl. In embodiments, R^(1D) is independentlyunsubstituted propyl. In embodiments, R^(1D) is independentlyunsubstituted isopropyl. In embodiments, R^(1D) is independentlyunsubstituted tert-butyl. In embodiments, R^(1D) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(1D) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(1D) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(1D) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1D) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(1D) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(1D) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(1D) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(1D) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(1D)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(1D) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(1D) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(1D) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1D) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(1D) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1D) is independently

hydrogen, —CX^(1D) ₃, —CHX^(1D) ₂, —CH₂X^(1D), —CN, —COOH, —CONH₂,R^(20D)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(20D)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(20D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(20D)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(20D)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(20D)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1D) is independently hydrogen, —CX^(1D) ₃, —CHX^(1D) ₂, —CH₂X^(1D),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(1D) is independently —F, —Cl, —Br, or —I. In embodiments,R^(1D) is independently hydrogen. In embodiments, R^(1D) isindependently unsubstituted methyl. In embodiments, R^(1D) isindependently unsubstituted ethyl.

R^(20D) is independently oxo,

halogen, —CX^(20D) ₃, —CHX^(20D) ₂, —CH₂X^(20D), —OCX^(20D) ₃,—OCH₂X^(20D), —OCHX^(20D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(21D)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(21D)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(21D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(21D)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(21D)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(21D)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(20D) isindependently oxo,halogen, —CX^(20D) ₃, —CHX^(20D) ₂, —CH₂X^(20D), —OCX^(20D) ₃,—OCH₂X^(20D), —OCHX^(20D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(20D) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(20D) is independently unsubstituted methyl. Inembodiments, R^(20D) is independently unsubstituted ethyl.

R^(21D) is independently oxo,

halogen, —CX^(21D) ₃, —CHX^(21D) ₂, —CH₂X^(21D), —OCX^(21D) ₃,—OCH₂X^(21D), —OCHX^(21D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(22D)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(22D)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(22D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(22D)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(22D)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(22D)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(21D) isindependently oxo,halogen, —CX^(21D) ₃, —CHX^(21D) ₂, —CH₂X^(21D), —OCX^(21D) ₃,—OCH₂X^(21D), —OCHX^(21D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(21D) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(21D) is independently unsubstituted methyl. Inembodiments, R^(21D) is independently unsubstituted ethyl.

R^(22D) is independently oxo,

halogen, —CX^(22D) ₃, —CHX^(22D) ₂, —CH₂X^(22D), —OCX^(22D) ₃,—OCH₂X^(22D), —OCHX^(22D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁—C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(22D) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(22D) is independently unsubstituted methyl. Inembodiments, R^(22D) is independently unsubstituted ethyl.

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₃, —CH₂X¹, orunsubstituted C₁-C₂ alkyl. In embodiments, R¹ is independently halogen,—CF₃, —CHF₂, —CH₂F, or —CH₃. In embodiments, R¹ is independently —F,—Cl, or —CF₃. In embodiments, R¹ is independently halogen, —SCX¹ ₃,—SCHX¹ ₂, —SCH₂X¹, or unsubstituted 2 to 3 membered heteroalkyl. Inembodiments, R¹ is independently halogen, —SCF₃, —SCHF₂, —SCH₂F, or—SCH₃. In embodiments, R¹ is independently —F, —Cl, —SCH₃, or —CF₃.

In embodiments, Ring B is aryl (e.g. C₆-C₁₂ aryl, C₆-C₁₀ aryl, or C₆aryl). In embodiments, Ring B is C₆-C₁₂ aryl. In embodiments, Ring B isC₆-C₁₀ aryl. In embodiments, Ring B is C₆ aryl. It will be understoodwhen z2 is 0, Ring B is unsubstituted (e.g., unsubstituted aryl orunsubstituted heteroaryl) in addition to the bond to —NH—. It will beunderstood when z2 is greater than 0 (e.g., 1, 2, 3, or 4), Ring B issubstituted with one or more R² substituents (e.g., R²-substituted arylor R²-substituted heteroaryl) in addition to the bond to —NH—.

In embodiments, Ring B is heteroaryl (e.g. 5 to 12 membered heteroaryl,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, Ring B is 5 to 12 memberedheteroaryl. In embodiments, Ring B is 5 to 10 membered heteroaryl. Inembodiments, Ring B is 5 to 9 membered heteroaryl. In embodiments, RingB is 5 to 6 membered heteroaryl.

In embodiments, Ring B is naphthyl. In embodiments, Ring B is biphenyl.In embodiments, Ring B is phenyl. In embodiments, Ring B is pyridyl. Inembodiments, Ring B is pyrazolyl. In embodiments, Ring B is imidazolyl.In embodiments, Ring B is oxazolyl. In embodiments, Ring B isisoxazolyl. In embodiments, Ring B is thiazolyl. In embodiments, Ring Bis furanyl. In embodiments, Ring B is pyrrolyl. In embodiments, Ring Bis thienyl. In embodiments, Ring B is 2-pyridyl. In embodiments, Ring Bis 3-pyridyl. In embodiments, Ring B is 4-pyridyl.

In embodiments, Ring B is indolinyl. In embodiments, Ring B isindazolyl. In embodiments, Ring B is benzimidazolyl. In embodiments,Ring B is benzoxazolyl. In embodiments, Ring B is azaindolyl. Inembodiments, Ring B is purinyl. In embodiments, Ring B is indolyl. Inembodiments, Ring B is pyrazinyl. In embodiments, Ring B is pyrrolyl. Inembodiments, Ring B is imidazolyl. In embodiments, Ring B is pyrazolyl.In embodiments, Ring B is triazolyl. In embodiments, Ring B istetrazolyl.

In embodiments, Ring B is a phenyl or 5 to 6 membered heteroaryl. Inembodiments, Ring B is a phenyl.

In embodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X²,—OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —SO_(n2)R^(2D), —SO_(v2)NR^(2A)R^(2B),—NHC(O)NR^(2A)R^(2B), —N(O)_(m2), —NR^(2A)R^(2B), —C(O)R^(2C),—C(O)—OR^(2C), —C(O)NR^(2A)R^(2B), —OR^(2D), —NR^(2A)SO₂R^(2D),—NR^(2A)C(O)R^(2C), —NR^(2A)C(O)OR^(2C), —NR^(2A)OR^(2C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. Two adjacent R² substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R² is independently —CX² ₃. In embodiments, R² isindependently —CHX² ₂. In embodiments, R² is independently —CH₂X². Inembodiments, R² is independently-OCX² ₃. In embodiments, R² isindependently-OCH₂X². In embodiments, R² is independently —OCHX² ₂. Inembodiments, R² is independently —CN. In embodiments, R² isindependently —SO_(n2)R^(2D). In embodiments, R² is independently—SR^(2D). In embodiments, R² is independently —SO_(v2)NR^(2A)R^(2B). Inembodiments, R² is independently —NHC(O)NR^(2A)R^(2B). In embodiments,R² is independently —N(O)_(m)2. In embodiments, R² is independently—NR^(2A)R^(2B). In embodiments, R² is independently —C(O)R^(2C). Inembodiments, R² is independently —C(O)—OR^(2C). In embodiments, R² isindependently —C(O)NR^(2A)R^(2B). In embodiments, R² is independently—OR^(2D). In embodiments, R² is independently —NR^(2A)SO₂R^(2D). Inembodiments, R² is independently —NR^(2A)C(O)R^(2C). In embodiments, R²is independently —NR^(2A)C(O)OR^(2C). In embodiments, R² isindependently —NR^(2A)OR^(2C). In embodiments, R² is independently —OH.In embodiments, R² is independently —NH₂. In embodiments, R² isindependently —COOH. In embodiments, R² is independently —CONH₂. Inembodiments, R² is independently —NO₂. In embodiments, R² isindependently —SH. In embodiments, R² is independently halogen. Inembodiments, R² is independently —F. In embodiments, R² is independently—Cl. In embodiments, R² is independently —Br. In embodiments, R² isindependently —I. In embodiments, R² is independently —CF₃. Inembodiments, R² is independently —CHF₂. In embodiments, R² isindependently —CH₂F. In embodiments, R² is independently —OCF₃. Inembodiments, R² is independently —OCH₂F. In embodiments, R² isindependently —OCHF₂. In embodiments, R² is independently —OCH₃. Inembodiments, R² is independently —OCH₂CH₃. In embodiments, R² isindependently —OCH₂CH₂CH₃. In embodiments, R² is independently—OCH(CH₃)₂. In embodiments, R² is independently —OC(CH₃)₃. Inembodiments, R² is independently —SCH₃. In embodiments, R² isindependently —SCH₂CH₃. In embodiments, R² is independently —SCH₂CH₂CH₃.In embodiments, R² is independently —SCH(CH₃)₂. In embodiments, R² isindependently —SC(CH₃)₃. In embodiments, R² is independently —CH₃. Inembodiments, R² is independently —CH₂CH₃. In embodiments, R² isindependently —CH₂CH₂CH₃. In embodiments, R² is independently —CH(CH₃)₂.In embodiments, R² is independently —C(CH₃)₃. In embodiments, R² isindependently —CH₂CH₂C(O)OCH₃. In embodiments, R² is independently—CH₂CH(CH₃)C(O)OCH₃. In embodiments, R² is independently —C(O)OCH₃. Inembodiments, R² is independently —C(O)OCH₂CH₃. In embodiments, R² isindependently —C(O)OCH(CH₃)₂. In embodiments, R² is independently—C(O)OC(CH₃)₃. In embodiments, R² is independently —NHC(O)CH₃. Inembodiments, R² is independently —NHC(O)CH₂CH₃. In embodiments, R² isindependently —NHC(O)CH(CH₃)₂. In embodiments, R² is independently—NHC(O)C(CH₃)₃. In embodiments, R² is independently —N₃.

In embodiments, R² is independently hydrogen, halogen, —CX² ₃, —CHX² ₂,—CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —SO_(n2)R^(2D),—SO_(v2)NR^(2A)R^(2B), —NHC(O)NR^(2A)R^(2B), —N(O)_(m2), —NR^(2A)R^(2B),—C(O)R^(2C), —C(O)—OR^(2C), —C(O)NR^(2A)R^(2B), —OR^(2D),—NR^(2A)SO₂R^(2D), —NR^(2A)C(O)R^(2C), —NR^(2A)C(O)OR^(2C),—NR^(2A)OR^(2C), substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R² is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R² is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² is independentlyunsubstituted methyl. In embodiments, R² is independently unsubstitutedethyl. In embodiments, R² is independently unsubstituted propyl. Inembodiments, R² is independently unsubstituted isopropyl. Inembodiments, R² is independently unsubstituted tert-butyl. Inembodiments, R² is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R² is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R² isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R² is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R² isindependently substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R² is independently unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R² isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R² is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R² isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R² is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R² is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R²is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R² is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R² is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R² is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X²,—OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R²³-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R²³-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R²³-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R²³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R²³-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R²³-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X² is independently —F, —Cl, —Br, or —I.

In embodiments, two adjacent R² substituents may be joined to form asubstituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R² substituents may be joined to form asubstituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, two adjacent R² substituents may be joined toform a substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, two adjacent R² substituents may be joined to form anunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, two adjacent R² substituents may be joined to form asubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, two adjacent R² substituents may be joined to form asubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4to 6 membered, 4 to 5 membered, or 5 to 6 membered In embodiments, twoadjacent R² substituents may be joined to form an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, twoadjacent R² substituents may be joined to form a substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,two adjacent R² substituents may be joined to form a substituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, two adjacent R²substituents may be joined to form an unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, two adjacent R² substituents may bejoined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, two adjacent R² substituents may be joined to form asubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, two adjacent R²substituents may be joined to form an unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R² substituents may be joined to form anR²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), R²³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R²³-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R²³-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, two adjacent R² substituents may be joined to form anunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(2.1) is independently hydrogen. In embodiments,R^(2.1) is independently-CX² ₃. In embodiments, R^(2.1) isindependently-CHX² ₂. In embodiments, R^(2.1) is independently —CH₂X².In embodiments, R^(2.1) is independently —OCX² ₃. In embodiments,R^(2.1) is independently —OCH₂X². In embodiments, R^(2.1) isindependently —OCHX² ₂. In embodiments, R^(2.1) is independently —CN. Inembodiments, R^(2.1) is independently —SO_(n2)R^(2D). In embodiments,R^(2.1) is independently —SO_(v2)NR^(2A)R^(2B). In embodiments, R^(2.1)is independently —NHC(O)NR^(2A)R^(2B). In embodiments, R^(2.1) isindependently —N_(m2). In embodiments, R^(2.1) is independently—NR^(2A)R^(2B). In embodiments, R^(2.1) is independently —C(O)R^(2C). Inembodiments, R^(2.1) is independently —C(O)—OR^(2C). In embodiments,R^(2.1) is independently —C(O)NR^(2A)R^(2B). In embodiments, R^(2.1) isindependently —OR^(2D). In embodiments, R^(2.1) is independently—NR^(2A)SO₂R^(2D). In embodiments, R^(2.1) is independently—NR^(2A)C(O)R^(2C). In embodiments, R^(2.1) is independently—NR^(2A)C(O)OR^(2C). In embodiments, R^(2.1) is independently—NR^(2A)OR^(2C). In embodiments, R^(2.1) is independently —OH. Inembodiments, R^(2.1) is independently —NH₂. In embodiments, R^(2.1) isindependently —COOH. In embodiments, R^(2.1) is independently —CONH₂. Inembodiments, R^(2.1) is independently —NO₂. In embodiments, R^(2.1) isindependently —SH. In embodiments, R^(2.1) is independently halogen. Inembodiments, R^(2.1) is independently-F. In embodiments, R^(2.1) isindependently-Cl. In embodiments, R^(2.1) is independently —Br. Inembodiments, R^(2.1) is independently —I. In embodiments, R^(2.1) isindependently —CF₃. In embodiments, R^(2.1) is independently —CHF₂. Inembodiments, R^(2.1) is independently —CH₂F. In embodiments, R^(2.1) isindependently —OCF₃. In embodiments, R^(2.1) is independently —OCH₂F. Inembodiments, R^(2.1) is independently —OCHF₂. In embodiments, R^(2.1) isindependently —OCH₃. In embodiments, R^(2.1) is independently —OCH₂CH₃.In embodiments, R^(2.1) is independently —OCH₂CH₂CH₃. In embodiments,R^(2.1) is independently —OCH(CH₃)₂. In embodiments, R^(2.1) isindependently —OC(CH₃)₃. In embodiments, R^(2.1) is independently —SCH₃.In embodiments, R^(2.1) is independently —SCH₂CH₃. In embodiments,R^(2.1) is independently —SCH₂CH₂CH₃. In embodiments, R^(2.1) isindependently —SCH(CH₃)₂. In embodiments, R^(2.1) is independently—SC(CH₃)₃. In embodiments, R^(2.1) is independently —CH₃. Inembodiments, R^(2.1) is independently —CH₂CH₃. In embodiments, R^(2.1)is independently —CH₂CH₂CH₃. In embodiments, R^(2.1) is independently—CH(CH₃)₂. In embodiments, R^(2.1) is independently —C(CH₃)₃. Inembodiments, R^(2.1) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(2.1) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(2.1) isindependently —C(O)OCH₃. In embodiments, R^(2.1) is independently—C(O)OCH₂CH₃. In embodiments, R^(2.1) is independently —C(O)OCH(CH₃)₂.In embodiments, R^(2.1) is independently —C(O)OC(CH₃)₃. In embodiments,R^(2.1) is independently —NHC(O)CH₃. In embodiments, R^(2.1) isindependently —NHC(O)CH₂CH₃. In embodiments, R^(2.1) is independently—NHC(O)CH(CH₃)₂. In embodiments, R^(2.1) is independently—NHC(O)C(CH₃)₃. In embodiments, R^(2.1) is independently —N₃.

In embodiments, R^(2.1) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.1) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2.1) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.1) is independentlyunsubstituted methyl. In embodiments, R^(2.1) is independentlyunsubstituted ethyl. In embodiments, R^(2.1) is independentlyunsubstituted propyl. In embodiments, R^(2.1) is independentlyunsubstituted isopropyl. In embodiments, R^(2.1) is independentlyunsubstituted tert-butyl. In embodiments, R^(2.1) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2.1) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(2.1) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2.1) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.1) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2.1) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.1) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2.1) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(2.1) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(2.1) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2.1) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(2.1) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(2.1) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(2.1) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(2.1)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(2.1) is independently hydrogen,

halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(2.1) isindependently hydrogen,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X² is independently —F, —Cl, —Br, or—I.

In embodiments, R^(2.2) is independently hydrogen. In embodiments,R^(2.2) is independently —CX² ₃. In embodiments, R^(2.2) isindependently —CHX² ₂. In embodiments, R^(2.2) is independently —CH₂X².In embodiments, R^(2.2) is independently —OCX² ₃. In embodiments,R^(2.2) is independently —OCH₂X². In embodiments, R^(2.2) isindependently —OCHX² ₂. In embodiments, R^(2.2) is independently —CN. Inembodiments, R^(2.2) is independently —SO_(n2)R^(2D). In embodiments,R^(2.2) is independently —SO_(v2)NR^(2A)R^(2B). In embodiments, R^(2.2)is independently —NHC(O)NR^(2A)R^(2B). In embodiments, R^(2.2) isindependently —N(O)_(m)2. In embodiments, R^(2.2) is independently—NR^(2A)R^(2B). In embodiments, R^(2.2) is independently —C(O)R^(2C). Inembodiments, R^(2.2) is independently —C(O)—OR^(2C). In embodiments,R^(2.2) is independently —C(O)NR^(2A)R^(2B). In embodiments, R^(2.2) isindependently —OR^(2D). In embodiments, R^(2.2) is independently—NR^(2A)SO₂R^(2D). In embodiments, R^(2.2) is independently—NR^(2A)C(O)R^(2C). In embodiments, R^(2.2) is independently—NR^(2A)C(O)OR^(2C). In embodiments, R^(2.2) isindependently-NR^(2A)OR^(2C). In embodiments, R^(2.2) isindependently-OH. In embodiments, R^(2.2) is independently —NH₂. Inembodiments, R^(2.2) is independently —COOH. In embodiments, R^(2.2) isindependently —CONH₂. In embodiments, R^(2.2) is independently —NO₂. Inembodiments, R^(2.2) is independently —SH. In embodiments, R^(2.2) isindependently halogen. In embodiments, R^(2.2) is independently —F. Inembodiments, R^(2.2) is independently —Cl. In embodiments, R^(2.2) isindependently —Br. In embodiments, R^(2.2) is independently —I. Inembodiments, R^(2.2) is independently —CF₃. In embodiments, R^(2.2) isindependently —CHF₂. In embodiments, R^(2.2) is independently —CH₂F. Inembodiments, R^(2.2) is independently —OCF₃. In embodiments, R^(2.2) isindependently —OCH₂F. In embodiments, R^(2.2) is independently —OCHF₂.In embodiments, R^(2.2) is independently —OCH₃. In embodiments, R^(2.2)is independently —OCH₂CH₃. In embodiments, R^(2.2) is independently—OCH₂CH₂CH₃. In embodiments, R^(2.2) is independently —OCH(CH₃)₂. Inembodiments, R^(2.2) is independently —OC(CH₃)₃. In embodiments, R^(2.2)is independently —SCH₃. In embodiments, R^(2.2) is independently—SCH₂CH₃. In embodiments, R^(2.2) is independently —SCH₂CH₂CH₃. Inembodiments, R^(2.2) is independently —SCH(CH₃)₂. In embodiments,R^(2.2) is independently —SC(CH₃)₃. In embodiments, R^(2.2) isindependently —CH₃. In embodiments, R^(2.2) is independently-CH₂CH₃. Inembodiments, R^(2.2) is independently-CH₂CH₂CH₃. In embodiments, R^(2.2)is independently —CH(CH₃)₂. In embodiments, R^(2.2) is independently—C(CH₃)₃. In embodiments, R^(2.2) is independently —CH₂CH₂C(O)OCH₃. Inembodiments, R^(2.2) is independently —CH₂CH(CH₃)C(O)OCH₃. Inembodiments, R^(2.2) is independently —C(O)OCH₃. In embodiments, R^(2.2)is independently —C(O)OCH₂CH₃. In embodiments, R^(2.2) is independently—C(O)OCH(CH₃)₂. In embodiments, R^(2.2) is independently —C(O)OC(CH₃)₃.In embodiments, R^(2.2) is independently —NHC(O)CH₃. In embodiments,R^(2.2) is independently —NHC(O)CH₂CH₃. In embodiments, R^(2.2) isindependently —NHC(O)CH(CH₃)₂. In embodiments, R^(2.2) is independently—NHC(O)C(CH₃)₃. In embodiments, R^(2.2) is independently —N₃.

In embodiments, R^(2.2) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.2) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2.2) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.2) is independentlyunsubstituted methyl. In embodiments, R^(2.2) is independentlyunsubstituted ethyl. In embodiments, R^(2.2) is independentlyunsubstituted propyl. In embodiments, R^(2.2) is independentlyunsubstituted isopropyl. In embodiments, R^(2.2) is independentlyunsubstituted tert-butyl. In embodiments, R^(2.2) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2.2) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(2.2) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2.2) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.2) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2.2) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.2) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2.2) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(2.2) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(2.2) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2.2) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(2.2) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(2.2) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(2.2) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(2.2)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(2.2) is independently hydrogen,

halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(2.2) isindependently hydrogen,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X² is independently —F, —Cl, —Br, or—I.

In embodiments, R^(2.3) is independently hydrogen. In embodiments,R^(2.3) is independently —CX² ₃. In embodiments, R^(2.3) isindependently —CHX² ₂. In embodiments, R^(2.3) is independently —CH₂X².In embodiments, R^(2.3) is independently —OCX² ₃. In embodiments,R^(2.3) is independently —OCH₂X². In embodiments, R^(2.3) isindependently —OCHX² ₂. In embodiments, R^(2.3) is independently —CN. Inembodiments, R^(2.3) is independently —SO_(n2)R^(2D). In embodiments,R^(2.3) is independently —SO_(v2)NR^(2A)R^(2B). In embodiments, R^(2.3)is independently —NHC(O)NR^(2A)R^(2B). In embodiments, R^(2.3) isindependently —N(O)_(m)2. In embodiments, R^(2.3) is independently—NR^(2A)R^(2B). In embodiments, R^(2.3) is independently —C(O)R^(2C). Inembodiments, R^(2.3) is independently —C(O)—OR^(2C). In embodiments,R^(2.3) is independently —C(O)NR^(2A)R^(2B). In embodiments, R^(2.3) isindependently —OR^(2D). In embodiments, R^(2.3) is independently—NR^(2A)SO₂R^(2D). In embodiments, R^(2.3) is independently—NR^(2A)C(O)R^(2C). In embodiments, R^(2.3) is independently—NR^(2A)C(O)OR^(2C). In embodiments, R^(2.3) is independently—NR^(2A)OR^(2C). In embodiments, R^(2.3) is independently —OH. Inembodiments, R^(2.3) is independently —NH₂. In embodiments, R^(2.3) isindependently —COOH. In embodiments, R^(2.3) is independently —CONH₂. Inembodiments, R^(2.3) is independently —NO₂. In embodiments, R^(2.3) isindependently —SH. In embodiments, R^(2.3) is independently halogen. Inembodiments, R^(2.3) is independently —F. In embodiments, R^(2.3) isindependently —Cl. In embodiments, R^(2.3) is independently —Br. Inembodiments, R^(2.3) is independently —I. In embodiments, R^(2.3) isindependently —CF₃. In embodiments, R^(2.3) is independently —CHF₂. Inembodiments, R^(2.3) is independently —CH₂F. In embodiments, R^(2.3) isindependently —OCF₃. In embodiments, R^(2.3) is independently —OCH₂F. Inembodiments, R^(2.3) is independently —OCHF₂. In embodiments, R^(2.3) isindependently —OCH₃. In embodiments, R^(2.3) is independently —OCH₂CH₃.In embodiments, R^(2.3) is independently —OCH₂CH₂CH₃. In embodiments,R^(2.3) is independently —OCH(CH₃)₂. In embodiments, R^(2.3) isindependently —OC(CH₃)₃. In embodiments, R^(2.3) is independently —SCH₃.In embodiments, R^(2.3) is independently —SCH₂CH₃. In embodiments,R^(2.3) is independently —SCH₂CH₂CH₃. In embodiments, R^(2.3) isindependently —SCH(CH₃)₂. In embodiments, R^(2.3) is independently—SC(CH₃)₃. In embodiments, R^(2.3) is independently —CH₃. Inembodiments, R^(2.3) is independently —CH₂CH₃. In embodiments, R^(2.3)is independently —CH₂CH₂CH₃. In embodiments, R^(2.3) is independently—CH(CH₃)₂. In embodiments, R^(2.3) is independently —C(CH₃)₃. Inembodiments, R^(2.3) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(2.3) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(2.3) isindependently —C(O)OCH₃. In embodiments, R^(2.3) is independently—C(O)OCH₂CH₃. In embodiments, R^(2.3) is independently —C(O)OCH(CH₃)₂.In embodiments, R^(2.3) is independently —C(O)OC(CH₃)₃. In embodiments,R^(2.3) is independently —NHC(O)CH₃. In embodiments, R^(2.3) isindependently —NHC(O)CH₂CH₃. In embodiments, R^(2.3) is independently—NHC(O)CH(CH₃)₂. In embodiments, R^(2.3) is independently—NHC(O)C(CH₃)₃. In embodiments, R^(2.3) is independently —N₃.

In embodiments, R^(2.3) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.3) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2.3) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.3) is independentlyunsubstituted methyl. In embodiments, R^(2.3) is independentlyunsubstituted ethyl. In embodiments, R^(2.3) is independentlyunsubstituted propyl. In embodiments, R^(2.3) is independentlyunsubstituted isopropyl. In embodiments, R^(2.3) is independentlyunsubstituted tert-butyl. In embodiments, R^(2.3) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2.3) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(2.3) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2.3) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.3) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2.3) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.3) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2.3) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(2.3) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(2.3) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2.3) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(2.3) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(2.3) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(2.3) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(2.3)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(2.3) is independently hydrogen,

halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(2.3) isindependently hydrogen,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X² is independently —F, —Cl, —Br, or—I.

In embodiments, R^(2.4) is independently hydrogen. In embodiments,R^(2.4) is independently —CX² ₃. In embodiments, R^(2.4) isindependently —CHX² ₂. In embodiments, R^(2.4) is independently —CH₂X².In embodiments, R^(2.4) is independently —OCX² ₃. In embodiments,R^(2.4) is independently —OCH₂X². In embodiments, R^(2.4) isindependently —OCHX² ₂. In embodiments, R^(2.4) is independently —CN. Inembodiments, R^(2.4) is independently —SO_(n2)R^(2D). In embodiments,R^(2.4) is independently —SO_(v2)NR^(2A)R^(2B). In embodiments, R^(2.4)is independently —NHC(O)NR^(2A)R^(2B). In embodiments, R^(2.4) isindependently —N(O)_(m2). In embodiments, R^(2.4) is independently—NR^(2A)R^(2B). In embodiments, R^(2.4) is independently —C(O)R^(2C). Inembodiments, R^(2.4) is independently —C(O)—OR^(2C). In embodiments,R^(2.4) is independently —C(O)NR^(2A)R^(2B). In embodiments, R^(2.4) isindependently-OR^(2D). In embodiments, R^(2.4) is independently—NR^(2A)SO₂R^(2D). In embodiments, R^(2.4) is independently—NR^(2A)C(O)R^(2C). In embodiments, R^(2.4) is independently—NR^(2A)C(O)OR^(2C). In embodiments, R^(2.4) is independently—NR^(2A)OR^(2C). In embodiments, R^(2.4) is independently —OH. Inembodiments, R^(2.4) is independently —NH₂. In embodiments, R^(2.4) isindependently —COOH. In embodiments, R^(2.4) is independently-CONH₂. Inembodiments, R^(2.4) is independently-NO₂. In embodiments, R^(2.4) isindependently —SH. In embodiments, R^(2.4) is independently halogen. Inembodiments, R^(2.4) is independently —F. In embodiments, R^(2.4) isindependently —Cl. In embodiments, R^(2.4) is independently —Br. Inembodiments, R^(2.4) is independently —I. In embodiments, R^(2.4) isindependently —CF₃. In embodiments, R^(2.4) is independently —CHF₂. Inembodiments, R^(2.4) is independently —CH₂F. In embodiments, R^(2.4) isindependently —OCF₃. In embodiments, R^(2.4) is independently —OCH₂F. Inembodiments, R^(2.4) is independently —OCHF₂. In embodiments, R^(2.4) isindependently —OCH₃. In embodiments, R^(2.4) is independently —OCH₂CH₃.In embodiments, R^(2.4) is independently —OCH₂CH₂CH₃. In embodiments,R^(2.4) is independently —OCH(CH₃)₂. In embodiments, R^(2.4) isindependently —OC(CH₃)₃. In embodiments, R^(2.4) is independently —SCH₃.In embodiments, R^(2.4) is independently —SCH₂CH₃. In embodiments,R^(2.4) is independently —SCH₂CH₂CH₃. In embodiments, R^(2.4) isindependently —SCH(CH₃)₂. In embodiments, R^(2.4) is independently—SC(CH₃)₃. In embodiments, R^(2.4) is independently —CH₃. Inembodiments, R^(2.4) is independently —CH₂CH₃. In embodiments, R^(2.4)is independently —CH₂CH₂CH₃. In embodiments, R^(2.4) is independently—CH(CH₃)₂. In embodiments, R^(2.4) is independently —C(CH₃)₃. Inembodiments, R^(2.4) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(2.4) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(2.4) isindependently —C(O)OCH₃. In embodiments, R^(2.4) is independently—C(O)OCH₂CH₃. In embodiments, R^(2.4) is independently —C(O)OCH(CH₃)₂.In embodiments, R^(2.4) is independently —C(O)OC(CH₃)₃. In embodiments,R^(2.4) is independently —NHC(O)CH₃. In embodiments, R^(2.4) isindependently —NHC(O)CH₂CH₃. In embodiments, R^(2.4) is independently—NHC(O)CH(CH₃)₂. In embodiments, R^(2.4) is independently—NHC(O)C(CH₃)₃. In embodiments, R^(2.4) is independently —N₃.

In embodiments, R^(2.4) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.4) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2.4) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.4) is independentlyunsubstituted methyl. In embodiments, R^(2.4) is independentlyunsubstituted ethyl. In embodiments, R^(2.4) is independentlyunsubstituted propyl. In embodiments, R^(2.4) is independentlyunsubstituted isopropyl. In embodiments, R^(2.4) is independentlyunsubstituted tert-butyl. In embodiments, R^(2.4) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2.4) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(2.4) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2.4) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.4) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2.4) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.4) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2.4) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(2.4) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(2.4) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2.4) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(2.4) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(2.4) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(2.4) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(2.4)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(2.4) is independently hydrogen,

halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²⁴ is independentlyhydrogen,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X² is independently —F, —Cl, —Br, or—I.

In embodiments, R^(2.5) is independently hydrogen. In embodiments,R^(2.5) is independently —CX² ₃. In embodiments, R^(2.5) isindependently —CHX² ₂. In embodiments, R^(2.5) is independently —CH₂X².In embodiments, R^(2.5) is independently —OCX² ₃. In embodiments,R^(2.5) is independently —OCH₂X². In embodiments, R^(2.5) isindependently —OCHX² ₂. In embodiments, R^(2.5) is independently —CN. Inembodiments, R^(2.5) is independently —SO_(n2)R^(2D). In embodiments,R^(2.5) is independently —SO_(v)2NR^(2A)R^(2B). In embodiments, R^(2.5)is independently —NHC(O)NR^(2A)R^(2B). In embodiments, R^(2.5) isindependently —N(O)_(m2). In embodiments, R^(2.5) is independently—NR^(2A)R^(2B). In embodiments, R^(2.5) is independently —C(O)R^(2C). Inembodiments, R^(2.5) is independently —C(O)—OR^(2C). In embodiments,R^(2.5) is independently —C(O)NR^(2A)R^(2B). In embodiments, R^(2.5) isindependently —OR^(2D). In embodiments, R^(2.5) is independently—NR^(2A)SO₂R^(2D). In embodiments, R^(2.5) is independently—NR^(2A)C(O)R^(2C). In embodiments, R^(2.5) is independently—NR^(2A)C(O)OR^(2C). In embodiments, R^(2.5) is independently—NR^(2A)OR^(2C). In embodiments, R^(2.5) is independently —OH. Inembodiments, R^(2.5) is independently —NH₂. In embodiments, R^(2.5) isindependently —COOH. In embodiments, R^(2.5) is independently —CONH₂. Inembodiments, R^(2.5) is independently —NO₂. In embodiments, R^(2.5) isindependently —SH. In embodiments, R^(2.5) is independently halogen. Inembodiments, R^(2.5) is independently —F. In embodiments, R^(2.5) isindependently —Cl. In embodiments, R^(2.5) is independently —Br. Inembodiments, R^(2.5) is independently —I. In embodiments, R^(2.5) isindependently —CF₃. In embodiments, R^(2.5) is independently —CHF₂. Inembodiments, R^(2.5) is independently —CH₂F. In embodiments, R^(2.5) isindependently —OCF₃. In embodiments, R^(2.5) is independently —OCH₂F. Inembodiments, R^(2.5) is independently —OCHF₂. In embodiments, R^(2.5) isindependently —OCH₃. In embodiments, R^(2.5) is independently —OCH₂CH₃.In embodiments, R^(2.5) is independently —OCH₂CH₂CH₃. In embodiments,R^(2.5) is independently —OCH(CH₃)₂. In embodiments, R^(2.5) isindependently —OC(CH₃)₃. In embodiments, R^(2.5) is independently —SCH₃.In embodiments, R^(2.5) is independently —SCH₂CH₃. In embodiments,R^(2.5) is independently —SCH₂CH₂CH₃. In embodiments, R^(2.5) isindependently —SCH(CH₃)₂. In embodiments, R^(2.5) is independently—SC(CH₃)₃. In embodiments, R^(2.5) is independently —CH₃. Inembodiments, R^(2.5) is independently —CH₂CH₃. In embodiments, R^(2.5)is independently —CH₂CH₂CH₃. In embodiments, R^(2.5) is independently—CH(CH₃)₂. In embodiments, R^(2.5) is independently —C(CH₃)₃. Inembodiments, R^(2.5) is independently —CH₂CH₂C(O)OCH₃. In embodiments,R^(2.5) is independently —CH₂CH(CH₃)C(O)OCH₃. In embodiments, R^(2.5) isindependently —C(O)OCH₃. In embodiments, R^(2.5) is independently—C(O)OCH₂CH₃. In embodiments, R^(2.5) is independently —C(O)OCH(CH₃)₂.In embodiments, R^(2.5) is independently —C(O)OC(CH₃)₃. In embodiments,R^(2.5) is independently —NHC(O)CH₃. In embodiments, R^(2.5) isindependently —NHC(O)CH₂CH₃. In embodiments, R^(2.5) is independently—NHC(O)CH(CH₃)₂. In embodiments, R^(2.5) is independently—NHC(O)C(CH₃)₃. In embodiments, R^(2.5) is independently —N₃.

In embodiments, R^(2.5) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.5) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2.5) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2.5) is independentlyunsubstituted methyl. In embodiments, R^(2.5) is independentlyunsubstituted ethyl. In embodiments, R^(2.5) is independentlyunsubstituted propyl. In embodiments, R^(2.5) is independentlyunsubstituted isopropyl. In embodiments, R^(2.5) is independentlyunsubstituted tert-butyl. In embodiments, R^(2.5) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2.5) is independently substituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered). In embodiments, R^(2.5) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2.5) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.5) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2.5) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2.5) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2.5) is independently substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered). In embodiments, R^(2.5) is independentlyunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R^(2.5) is independently substituted or unsubstituted aryl (e.g.,C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2.5) is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments,R^(2.5) is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl). In embodiments, R^(2.5) is independently substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(2.5) isindependently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^(2.5)is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(2.5) is independently hydrogen,

halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R²³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R^(2.5) isindependently hydrogen,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X² is independently —F, —Cl, —Br, or—I.

R²³ is independently oxo,

halogen, —CX²³ ₃, —CHX²³ ₂, —CH₂X²³, —OCX²³ ₃, —OCH₂X²³, —OCHX²³ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R²⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R²⁴-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R²⁴-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁴-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁴-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁴-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²³ is independentlyoxo,halogen, —CX²³ ₃, —CHX²³ ₂, —CH₂X²³, —OCX²³ ₃, —OCH₂X²³, —OCHX²³ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²³ is independently —F, —Cl, —Br, or —I. In embodiments, R²³ isindependently unsubstituted methyl. In embodiments, R²³ is independentlyunsubstituted ethyl.

R²⁴ is independently oxo,

halogen, —CX²⁴ ₃, —CHX²⁴ ₂, —CH₂X²⁴, —OCX²⁴ ₃, —OCH₂X²⁴, —OCHX²⁴ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R²⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R²⁵-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R²⁵-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁵-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁵-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²⁴ is independentlyoxo,halogen, —CX²⁴ ₃, —CHX²⁴ ₂, —CH₂X²⁴, —OCX²⁴ ₃, —OCH₂X²⁴, —OCHX²⁴ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁴ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁴ isindependently unsubstituted methyl. In embodiments, R²⁴ is independentlyunsubstituted ethyl.

R²⁵ is independently oxo,

halogen, —CX²⁵ ₃, —CHX²⁵ ₂, —CH₂X²⁵, —OCX²⁵ ₃, —OCH₂X²⁵, —OCHX²⁵ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁵ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁵ isindependently unsubstituted methyl. In embodiments, R²⁵ is independentlyunsubstituted ethyl.

In embodiments, R^(2A) is independently hydrogen. In embodiments, R^(2A)is independently —CX^(2A) ₃. In embodiments, R^(2A) is independently—CHX^(2A) ₂. In embodiments, R^(2A) is independently —CH₂X^(2A). Inembodiments, R^(2A) is independently —CN. In embodiments, R^(2A) isindependently —COOH. In embodiments, R^(2A) is independently —CONH₂. Inembodiments, X^(2A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(2A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2A) isindependently substituted alkyl (e.g., C₁-C₈, C₁—C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2A) is independentlyunsubstituted methyl. In embodiments, R^(2A) is independentlyunsubstituted ethyl. In embodiments, R^(2A) is independentlyunsubstituted propyl. In embodiments, R^(2A) is independentlyunsubstituted isopropyl. In embodiments, R^(2A) is independentlyunsubstituted tert-butyl. In embodiments, R^(2A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(2A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(2A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(2A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(2A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(2A) is independently

hydrogen, —CX^(2A) ₃, —CHX^(2A) ₂, —CH₂X^(2A), —CN, —COOH, —CONH₂,R^(23A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(23A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(23A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(23A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(23A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(23A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2A) is independently hydrogen, —CX^(2A) ₃, —CHX^(2A) ₂, —CH₂X^(2A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(2A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(2A) is independently hydrogen. In embodiments, R^(2A) isindependently unsubstituted methyl. In embodiments, R^(2A) isindependently unsubstituted ethyl.

In embodiments, R^(2A) and R^(2B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(23A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(23A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(23A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2A)and R^(2B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(23A) is independently oxo,

halogen, —CX^(23A) ₃, —CHX^(23A) ₂, —CH₂X^(23A), —OCX^(23A) ₃,—OCH₂X^(23A), —OCHX^(23A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(24A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(24A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(24A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(24A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(24A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(24A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(23A) isindependently oxo,halogen, —CX^(23A) ₃, —CHX^(23A) ₂, —CH₂X^(23A), —OCX^(23A) ₃,—OCH₂X^(23A), —OCHX^(23A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(23A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(23A) is independently unsubstituted methyl. Inembodiments, R^(23A) is independently unsubstituted ethyl.

R^(24A) is independently oxo,

halogen, —CX^(24A) ₃, —CHX^(24A) ₂, —CH₂X^(24A), —OCX^(24A) ₃,—OCH₂X^(24A), —OCHX^(24A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(25A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(25A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(25A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(25A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(25A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(25A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(24A) isindependently oxo,halogen, —CX^(24A) ₃, —CHX^(24A) ₂, —CH₂X^(24A), —OCX^(24A) ₃,—OCH₂X^(24A), —OCHX^(24A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(24A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(24A) is independently unsubstituted methyl. Inembodiments, R^(24A) is independently unsubstituted ethyl.

R^(25A) is independently oxo,

halogen, —CX^(25A) ₃, —CHX^(25A) ₂, —CH₂X^(25A), —OCX^(25A) ₃,—OCH₂X^(25A), —OCHX^(25A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(25A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(25A) is independently unsubstituted methyl. Inembodiments, R^(25A) is independently unsubstituted ethyl.

In embodiments, R^(2B) is independently hydrogen. In embodiments, R^(2B)is independently —CX^(2B) ₃. In embodiments, R^(2B) is independently—CHX^(2B) ₂. In embodiments, R^(2B) is independently —CH₂X^(2B). Inembodiments, R^(2B) is independently —CN. In embodiments, R^(2B) isindependently —COOH. In embodiments, R^(2B) is independently —CONH₂. Inembodiments, X^(2B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(2B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2B) is independentlyunsubstituted methyl. In embodiments, R^(2B) is independentlyunsubstituted ethyl. In embodiments, R^(2B) is independentlyunsubstituted propyl. In embodiments, R^(2B) is independentlyunsubstituted isopropyl. In embodiments, R^(2B) is independentlyunsubstituted tert-butyl. In embodiments, R^(2B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(2B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(2B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(2B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(2B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(2A) and R^(2B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2A)and R^(2B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2A) and R^(2B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(2A) and R^(2B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2A) and R^(2B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2A) and R^(2B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(2B) is independently

hydrogen, —CX^(2B) ₃, —CHX^(2B) ₂, —CH₂X^(2B), —CN, —COOH, —CONH₂,R^(23B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(23B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(23B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(23B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(23B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(23B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2B) is independently hydrogen, —CX^(2B) ₃, —CHX^(2B) ₂, —CH₂X^(2B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(2B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(2B) is independently hydrogen. In embodiments, R^(2B) isindependently unsubstituted methyl. In embodiments, R^(2B) isindependently unsubstituted ethyl.

In embodiments, R^(2A) and R^(2B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(23B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(23B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(23B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2A)and R^(2B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(23B) is independently oxo,

halogen, —CX^(23B) ₃, —CHX^(23B) ₂, —CH₂X^(23B), —OCX^(23B) ₃,—OCH₂X^(23B), —OCHX^(23B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(24B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(24B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(24B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(24B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(24B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(24B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(23B) isindependently oxo,halogen, —CX^(23B) ₃, —CHX^(23B) ₂, —CH₂X^(23B), —OCX^(23B) ₃,—OCH₂X^(23B), —OCHX^(23B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(23B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(23B) is independently unsubstituted methyl. Inembodiments, R^(23B) is independently unsubstituted ethyl.

R^(24B) is independently oxo,

halogen, —CX^(24B) ₃, —CHX^(24B) ₂, —CH₂X^(24B), —OCX^(24B) ₃,—OCH₂X^(24B), —OCHX^(24B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(25B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(25B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(25B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(25B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(25B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(25B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(24B) isindependently oxo,halogen, —CX^(24B) ₃, —CHX^(24B) ₂, —CH₂X^(24B), —OCX^(24B) ₃,—OCH₂X^(24B), —OCHX^(24B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(24B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(24B) is independently unsubstituted methyl. Inembodiments, R^(24B) is independently unsubstituted ethyl.

R^(25B) is independently oxo,

halogen, —CX^(25B) ₃, —CHX^(25B) ₂, —CH₂X^(25B), —OCX^(25B) ₃,—OCH₂X^(25B), —OCHX^(25B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(25B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(25B) is independently unsubstituted methyl. Inembodiments, R^(25B) is independently unsubstituted ethyl.

In embodiments, R^(2C) is independently hydrogen. In embodiments, R^(2C)is independently —CX^(2C) ₃. In embodiments, R^(2C) is independently—CHX^(2C) ₂. In embodiments, R^(2C) is independently —CH₂X^(2C). Inembodiments, R^(2C) is independently —CN. In embodiments, R^(2C) isindependently —COOH. In embodiments, R^(2C) is independently —CONH₂. Inembodiments, X^(2C) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(2C) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2C) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2C) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2C) is independentlyunsubstituted methyl. In embodiments, R^(2C) is independentlyunsubstituted ethyl. In embodiments, R^(2C) is independentlyunsubstituted propyl. In embodiments, R^(2C) is independentlyunsubstituted isopropyl. In embodiments, R^(2C) is independentlyunsubstituted tert-butyl. In embodiments, R^(2C) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2C) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(2C) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2C) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2C) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2C) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2C) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2C) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(2C) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2C)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(2C) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2C) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(2C) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2C) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2C) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(2C) is independently

hydrogen, —CX^(2C) ₃, —CHX^(2C) ₂, —CH₂X^(2C), —CN, —COOH, —CONH₂,R^(23C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(23C)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(23C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(23C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(23C)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(23C)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2C) is independently hydrogen, —CX^(2C) ₃, —CHX^(2C) ₂, —CH₂X^(2C),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(2C) is independently —F, —Cl, —Br, or —I. In embodiments,R^(2C) is independently hydrogen. In embodiments, R^(2C) isindependently unsubstituted methyl. In embodiments, R^(2C) isindependently unsubstituted ethyl.

R^(23C) is independently oxo,

halogen, —CX^(23C) ₃, —CHX^(23C) ₂, —CH₂X^(23C), —OCX^(23C) ₃,—OCH₂X^(23C), —OCHX^(23C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(24C)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(24C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(24C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(24C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(24C)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(24C)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(23C) isindependently oxo,halogen, —CX^(23C) ₃, —CHX^(23C) ₂, —CH₂X^(23C), —OCX^(23C) ₃,—OCH₂X^(23C), —OCHX^(23C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(23C) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(23C) is independently unsubstituted methyl. Inembodiments, R^(23C) is independently unsubstituted ethyl.

R^(24C) is independently oxo,

halogen, —CX^(24C) ₃, —CHX^(24C) ₂, —CH₂X^(24C), —OCX^(24C) ₃,—OCH₂X^(24C), —OCHX^(24C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(25C)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(25C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(25C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(25C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(25C)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(25C)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(24C) isindependently oxo,halogen, —CX^(24C) ₃, —CHX^(24C) ₂, —CH₂X^(24C), —OCX^(24C) ₃,—OCH₂X^(24C), —OCHX^(24C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(24C) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(24C) is independently unsubstituted methyl. Inembodiments, R^(24C) is independently unsubstituted ethyl.

R^(25C) is independently oxo,

halogen, —CX^(25C) ₃, —CHX^(25C) ₂, —CH₂X^(25C), —OCX^(25C) ₃,—OCH₂X^(25C), —OCHX^(25C) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(25C) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(25C) is independently unsubstituted methyl. Inembodiments, R^(25C) is independently unsubstituted ethyl.

In embodiments, R^(2D) is independently hydrogen. In embodiments, R^(2D)is independently —CX^(2D) ₃. In embodiments, R^(2D) is independently—CHX^(2D) ₂. In embodiments, R^(2D) is independently —CH₂X^(2D). Inembodiments, R^(2D) is independently —CN. In embodiments, R^(2D) isindependently —COOH. In embodiments, R^(2D) is independently —CONH₂. Inembodiments, X^(2D) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(2D) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2D) isindependently substituted alkyl (e.g., C₁-C₈, C₁—C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(2D) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(2D) is independentlyunsubstituted methyl. In embodiments, R^(2D) is independentlyunsubstituted ethyl. In embodiments, R^(2D) is independentlyunsubstituted propyl. In embodiments, R^(2D) is independentlyunsubstituted isopropyl. In embodiments, R^(2D) is independentlyunsubstituted tert-butyl. In embodiments, R^(2D) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(2D) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(2D) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(2D) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2D) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(2D) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(2D) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(2D) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(2D) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(2D)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(2D) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(2D) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(2D) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2D) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(2D) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(2D) is independently

hydrogen, —CX^(2D) ₃, —CHX^(2D) ₂, —CH₂X^(2D), —CN, —COOH, —CONH₂,R^(23D)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(23D)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(23D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(23D)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(23D)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(23D)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2D) is independently hydrogen, —CX^(2D) ₃, —CHX^(2D) ₂, —CH₂X^(2D),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(2D) is independently —F, —Cl, —Br, or —I. In embodiments,R^(2D) is independently hydrogen. In embodiments, R^(2D) isindependently unsubstituted methyl. In embodiments, R^(2D) isindependently unsubstituted ethyl.

R^(23D) is independently oxo,

halogen, —CX^(23D) ₃, —CHX^(23D) ₂, —CH₂X^(23D), —OCX^(23D) ₃,—OCH₂X^(23D), —OCHX^(23D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(24D)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(24D)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(24D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(24D)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(24D)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(24D)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(23D) isindependently oxo,halogen, —CX^(23D) ₃, —CHX^(23D) ₂, —CH₂X^(23D), —OCX^(23D) ₃,—OCH₂X^(23D), —OCHX^(23D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(23D) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(23D) is independently unsubstituted methyl. Inembodiments, R^(23D) is independently unsubstituted ethyl.

R^(24D) is independently oxo,

halogen, —CX^(24D) ₃, —CHX^(24D) ₂, —CH₂X^(24D), —OCX^(24D) ₃,—OCH₂X^(24D), —OCHX^(24D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(25D)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(25D)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(25D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(25D)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(25D)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(25D)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(24D) isindependently oxo,halogen, —CX^(24D) ₃, —CHX^(24D) ₂, —CH₂X^(24D), —OCX^(24D) ₃,—OCH₂X^(24D), —OCHX^(24D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(24D) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(24D) is independently unsubstituted methyl. Inembodiments, R^(24D) is independently unsubstituted ethyl.

R^(25D) is independently oxo,

halogen, —CX^(25D) ₃, —CHX^(25D) ₂, —CH₂X^(25D), —OCX^(25D) ₃,—OCH₂X^(25D), —OCHX^(25D) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(25D) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(25D) is independently unsubstituted methyl. Inembodiments, R^(25D) is independently unsubstituted ethyl.

In embodiments, R² is independently —OCX² ₃, —OCH₂X², —OCHX² ₂,—C(O)R^(2C), —C(O)OR^(2C), —OR^(2D), or —NR^(2A)C(O)R^(2C); and eachR^(2A), R^(2B), R^(2C), and R^(2D) is independently hydrogen, —CX₃,—CHX₂, —CH₂X, or unsubstituted C₁-C₂ alkyl. In embodiments, R² isindependently —OCF₃, —OCH₂F, —OCHF₂, —C(O)OH, —C(O)OCH₂CH₃, —OCH₃, or—NHC(O)CH₃.

In embodiments, R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂,—CH₂X³, —OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —SO_(n3)R^(3A),—SO_(v3)NR^(3A)R^(3B), —NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B),—C(O)R^(3A), —C(O)OR^(3A), —C(O)NR^(3A)R^(3B), —OR^(3A),—NR^(3A)SO₂R^(3B), —NR^(3A)C(O)R^(3B), —NR^(3A)C(O)OR^(3B),—NR^(3A)OR^(3B), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R³ is independently hydrogen. In embodiments, R³ isindependently —CX³ ₃. In embodiments, R³ is independently —CHX³ ₂. Inembodiments, R³ is independently —CH₂X³. In embodiments, R³ isindependently —OCX³ ₃. In embodiments, R³ is independently —OCH₂X³. Inembodiments, R³ is independently —OCHX³ ₂. In embodiments, R³ isindependently —CN. In embodiments, R³ is independently —C(O)R^(3A). Inembodiments, R³ is independently —C(O)OR^(3A). In embodiments, R³ isindependently —C(O)NR^(3A)R^(3B). In embodiments, R³ is independently—OR^(3A). In embodiments, R³ is independently —OH. In embodiments, R³ isindependently —COOH. In embodiments, R³ is independently —CONH₂. Inembodiments, R³ is independently —CF₃. In embodiments, R³ isindependently —CHF₂. In embodiments, R³ is independently —CH₂F. Inembodiments, R³ is independently —OCF₃. In embodiments, R³ isindependently —OCH₂F. In embodiments, R³ is independently —OCHF₂. Inembodiments, R³ is independently —OCH₃. In embodiments, R³ isindependently —OCH₂CH₃. In embodiments, R³ is independently —OCH₂CH₂CH₃.In embodiments, R³ is independently —OCH(CH₃)₂. In embodiments, R³ isindependently —OC(CH₃)₃. In embodiments, R³ is independently —CH₃. Inembodiments, R³ is independently —CH₂CH₃. In embodiments, R³ isindependently —CH₂CH₂CH₃. In embodiments, R³ is independently —CH(CH₃)₂.In embodiments, R³ is independently —C(CH₃)₃. In embodiments, R³ isindependently unsubstituted methyl. In embodiments, R³ is independentlyunsubstituted ethyl. In embodiments, R³ is independently unsubstitutedpropyl. In embodiments, R³ is independently unsubstituted isopropyl. Inembodiments, R³ is independently unsubstituted n-propyl. In embodiments,R³ is independently unsubstituted butyl. In embodiments, R³ isindependently unsubstituted n-butyl. In embodiments, R³ is independentlyunsubstituted t-butyl. In embodiments, R³ is independently unsubstitutediso-butyl. In embodiments, R³ is independently unsubstituted C₁-C₈alkyl. In embodiments, R³ is independently halo-substituted methyl. Inembodiments, R³ is independently halo-substituted ethyl. In embodiments,R³ is independently halo-substituted isopropyl. In embodiments, R³ isindependently halo-substituted n-propyl. In embodiments, R³ isindependently halo-substituted n-butyl. In embodiments, R³ isindependently halo-substituted t-butyl. In embodiments, R³ isindependently halo-substituted C₁-C₈ alkyl. In embodiments, R³ isindependently —N₃.

In embodiments, R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —C(O)R^(3A), —C(O)OR^(3A),—C(O)NR^(3A)R^(3B), —OR^(3A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —C(O)R^(3A), —C(O)—OR^(3A),—C(O)NR^(3A)R^(3B), —OR^(3A), substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R³ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R³ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ is independentlyunsubstituted methyl. In embodiments, R³ is independently unsubstitutedethyl. In embodiments, R³ is independently unsubstituted propyl. Inembodiments, R³ is independently unsubstituted isopropyl. Inembodiments, R³ is independently unsubstituted tert-butyl. Inembodiments, R³ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R³ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R³ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R³ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R³ isindependently substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R³ is independently unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R³ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R³ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R³ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R³ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R³ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R³is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R³ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R³ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R³ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —C(O)R^(3A), —C(O)—OR^(3A),—C(O)NR^(3A)R^(3B), —OR^(3A), R²⁶-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R²⁶-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), R²⁶-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁶-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R³is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³,—OCHX³ ₂, —CN, —C(O)—OH, —C(O)NH₂, —OH, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X³ is independently —F, —Cl, —Br, or —I.

R²⁶ is independently oxo,

halogen, —CX²⁶ ₃, —CHX²⁶ ₂, —CH₂X²⁶, —OCX²⁶ ₃, —OCH₂X²⁶, —OCHX²⁶ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R²⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R²⁷-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R²⁷-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁷-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁷-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁷-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²⁶ is independentlyoxo,halogen, —CX²⁶ ₃, —CHX²⁶ ₂, —CH₂X²⁶, —OCX²⁶ ₃, —OCH₂X²⁶, —OCHX²⁶ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁶ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁶ isindependently unsubstituted methyl. In embodiments, R²⁶ is independentlyunsubstituted ethyl.

R²⁷ is independently oxo,

halogen, —CX²⁷ ₃, —CHX²⁷ ₂, —CH₂X²⁷, —OCX²⁷ ₃, —OCH₂X²⁷, —OCHX²⁷ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R²⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R²⁸-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁸-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R²⁸-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R²⁸-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²⁷ is independentlyoxo,halogen, —CX²⁷ ₃, —CHX²⁷ ₂, —CH₂X²⁷, —OCX²⁷ ₃, —OCH₂X²⁷, —OCHX²⁷ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁷ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁷ isindependently unsubstituted methyl. In embodiments, R²⁷ is independentlyunsubstituted ethyl.

R²⁸ is independently oxo,

halogen, —CX²⁸ ₃, —CHX²⁸ ₂, —CH₂X²⁸, —OCX²⁸ ₃, —OCH₂X²⁸, —OCHX²⁸ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁸ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁸ isindependently unsubstituted methyl. In embodiments, R²⁸ is independentlyunsubstituted ethyl.

In embodiments, R^(3A) is independently hydrogen. In embodiments, R^(3A)is independently —CX^(3A) ₃. In embodiments, R^(3A) is independently—CHX^(3A) ₂. In embodiments, R^(3A) is independently —CH₂X^(3A). Inembodiments, R^(3A) is independently —CN. In embodiments, R^(3A) isindependently —COOH. In embodiments, R^(3A) is independently —CONH₂. Inembodiments, X^(3A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(3A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(3A) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(3A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(3A) is independentlyunsubstituted methyl. In embodiments, R^(3A) is independentlyunsubstituted ethyl. In embodiments, R^(3A) is independentlyunsubstituted propyl. In embodiments, R^(3A) is independentlyunsubstituted isopropyl. In embodiments, R^(3A) is independentlyunsubstituted tert-butyl. In embodiments, R^(3A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(3A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(3A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(3A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(3A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(3A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(3A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(3A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(3A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(3A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(3A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(3A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(3A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(3A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(3A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(3A) is independently

hydrogen, —CX^(3A) ₃, —CHX^(3A) ₂, —CH₂X^(3A), —CN, —COOH, —CONH₂,R^(26A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(26A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(26A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(26A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(26A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3A) is independently hydrogen, —CX^(3A) ₃, —CHX^(3A) ₂, —CH₂X^(3A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(3A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(3A) is independently hydrogen. In embodiments, R^(3A) isindependently unsubstituted methyl. In embodiments, R^(3A) isindependently unsubstituted ethyl.

In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(26A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(26A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(3A)and R^(3B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(26A) is independently oxo,

halogen, —CX^(26A) ₃, —CHX^(26A) ₂, —CH₂X^(26A), —OCX^(26A) ₃,—OCH₂X^(26A), —OCHX^(26A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(27A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(27A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(27A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(27A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(27A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(27A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(26A) isindependently oxo,halogen, —CX^(26A) ₃, —CHX^(26A) ₂, —CH₂X^(26A), —OCX^(26A) ₃,—OCH₂X^(26A), —OCHX^(26A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(26A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(26A) is independently unsubstituted methyl. Inembodiments, R^(26A) is independently unsubstituted ethyl.

R^(27A) is independently oxo,

halogen, —CX^(27A) ₃, —CHX^(27A) ₂, —CH₂X^(27A), —OCX^(27A) ₃,—OCH₂X^(27A), —OCHX^(27A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(28A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(28A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(28A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(28A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(28A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(28A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(27A) isindependently oxo,halogen, —CX^(27A) ₃, —CHX^(27A) ₂, —CH₂X^(27A), —OCX^(27A) ₃,—OCH₂X^(27A), —OCHX^(27A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(27A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(27A) is independently unsubstituted methyl. Inembodiments, R^(27A) is independently unsubstituted ethyl.

R^(28A) is independently oxo,

halogen, —CX^(28A) ₃, —CHX^(28A) ₂, —CH₂X^(28A), —OCX^(28A) ₃,—OCH₂X^(28A), —OCHX^(28A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(28A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(28A) is independently unsubstituted methyl. Inembodiments, R^(28A) is independently unsubstituted ethyl.

In embodiments, R^(3B) is independently hydrogen. In embodiments, R^(3B)is independently —CX^(3B) ₃. In embodiments, R^(3B) is independently—CHX^(3B) ₂. In embodiments, R^(3B) is independently-CH₂X^(3B). Inembodiments, R^(3B) is independently-CN. In embodiments, R^(3B) isindependently —COOH. In embodiments, R^(3B) is independently —CONH₂. Inembodiments, X^(3B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(3B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(3B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(3B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(3B) is independentlyunsubstituted methyl. In embodiments, R^(3B) is independentlyunsubstituted ethyl. In embodiments, R^(3B) is independentlyunsubstituted propyl. In embodiments, R^(3B) is independentlyunsubstituted isopropyl. In embodiments, R^(3B) is independentlyunsubstituted tert-butyl. In embodiments, R^(3B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(3B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(3B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(3B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(3B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(3B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(3B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(3B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(3B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(3B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(3B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(3B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(3B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(3B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(3B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(3A)and R^(3B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(3A) and R^(3B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(3B) is independently

hydrogen, —CX^(3B) ₃, —CHX^(3B) ₂, —CH₂X^(3B), —CN, —COOH, —CONH₂,R^(26B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(26B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(26B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(26B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(26B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3B) is independently hydrogen, —CX^(3B) ₃, —CHX^(3B) ₂, —CH₂X^(3B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(3B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(3B) is independently hydrogen. In embodiments, R^(3B) isindependently unsubstituted methyl. In embodiments, R^(3B) isindependently unsubstituted ethyl.

In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(26B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(26B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(3A)and R^(3B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(26B) is independently oxo,

halogen, —CX^(26B) ₃, —CHX^(26B) ₂, —CH₂X^(26B), —OCX^(26B) ₃,—OCH₂X^(26B), —OCHX^(26B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(27B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(27B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(27B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(27B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(27B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(27B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(26B) isindependently oxo,halogen, —CX^(26B) ₃, —CHX^(26B) ₂, —CH₂X^(26B), —OCX^(26B) ₃,—OCH₂X^(26B), —OCHX^(26B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(26B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(26B) is independently unsubstituted methyl. Inembodiments, R^(26B) is independently unsubstituted ethyl.

R^(27B) is independently oxo,

halogen, —CX^(27B) ₃, —CHX^(27B) ₂, —CH₂X^(27B), —OCX^(27B) ₃,—OCH₂X^(27B), —OCHX^(27B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(28B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(28B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(28B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(28B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(28B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(28B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(27B) isindependently oxo,halogen, —CX^(27B) ₃, —CHX^(27B) ₂, —CH₂X^(27B), —OCX^(27B) ₃,—OCH₂X^(27B), —OCHX^(27B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(27B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(27B) is independently unsubstituted methyl. Inembodiments, R^(27B) is independently unsubstituted ethyl.

R^(28B) is independently oxo,

halogen, —CX^(28B) ₃, —CHX^(28B) ₂, —CH₂X^(28B), —OCX^(28B) ₃,—OCH₂X^(28B), —OCHX^(28B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(28B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(28B) is independently unsubstituted methyl. Inembodiments, R^(28B) is independently unsubstituted ethyl.

In embodiments, R³ is —CX³ ₃, —CHX³ ₂, —CH₂X³, or unsubstituted C₁-C₃alkyl. In embodiments, R³ is unsubstituted methyl.

In embodiments, R⁴ is independently hydrogen. In embodiments, R⁴ isindependently-CX⁴ ₃. In embodiments, R⁴ is independently-CHX⁴ ₂. Inembodiments, R⁴ is independently —CH₂X⁴. In embodiments, R⁴ isindependently —C(O)R^(4A). In embodiments, R⁴ is independently—C(O)OR^(4A). In embodiments, R⁴ is independently —C(O)NR^(4A)R^(4B). Inembodiments, R⁴ is independently —COOH. In embodiments, R⁴ isindependently —CONH₂. In embodiments, R⁴ is independently —CF₃. Inembodiments, R⁴ is independently —CHF₂. In embodiments, R⁴ isindependently —CH₂F. In embodiments, R⁴ is independently —CH₃. Inembodiments, R⁴ is independently —CH₂CH₃. In embodiments, R⁴ isindependently —CH₂CH₂CH₃. In embodiments, R⁴ is independently —CH(CH₃)₂.In embodiments, R⁴ is independently —C(CH₃)₃. In embodiments, R⁴ isindependently unsubstituted methyl. In embodiments, R⁴ is independentlyunsubstituted ethyl. In embodiments, R⁴ is independently unsubstitutedpropyl. In embodiments, R⁴ is independently unsubstituted isopropyl. Inembodiments, R⁴ is independently unsubstituted n-propyl. In embodiments,R⁴ is independently unsubstituted butyl. In embodiments, R⁴ isindependently unsubstituted n-butyl. In embodiments, R⁴ is independentlyunsubstituted t-butyl. In embodiments, R⁴ is independently unsubstitutediso-butyl. In embodiments, R⁴ is independently unsubstituted C₁-C₈alkyl. In embodiments, R⁴ is independently halo-substituted methyl. Inembodiments, R⁴ is independently halo-substituted ethyl. In embodiments,R⁴ is independently halo-substituted isopropyl. In embodiments, R⁴ isindependently halo-substituted n-propyl. In embodiments, R⁴ isindependently halo-substituted n-butyl. In embodiments, R⁴ isindependently halo-substituted t-butyl. In embodiments, R⁴ isindependently halo-substituted C₁-C₈ alkyl.

In embodiments, R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,—C(O)R^(4A), —C(O)—OR^(4A), —C(O)NR^(4A)R^(4B), substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁴ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R⁴ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ is independentlyunsubstituted methyl. In embodiments, R⁴ is independently unsubstitutedethyl. In embodiments, R⁴ is independently unsubstituted propyl. Inembodiments, R⁴ is independently unsubstituted isopropyl. Inembodiments, R⁴ is independently unsubstituted tert-butyl. Inembodiments, R⁴ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R⁴ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁴ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R⁴ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁴ isindependently substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁴ is independently unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁴ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R⁴ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R⁴ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁴ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁴ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁴is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R⁴ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁴ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁴ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,—C(O)R^(4A), —C(O)—OR^(4A), —C(O)NR^(4A)R^(4B), R²⁹-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R²⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R²⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), R²⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R²⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R²⁹-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,—C(O)—OH, —C(O)NH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X⁴ is independently —F, —Cl, —Br, or —I.

R²⁹ is independently oxo,

halogen, —CX²⁹ ₃, —CHX²⁹ ₂, —CH₂X²⁹, —OCX²⁹ ₃, —OCH₂X²⁹, —OCHX²⁹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³⁰-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³⁰-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R³⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R²⁹ is independentlyoxo,halogen, —CX²⁹ ₃, —CHX²⁹ ₂, —CH₂X²⁹, —OCX²⁹ ₃, —OCH₂X²⁹, —OCHX²⁹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X²⁹ is independently —F, —Cl, —Br, or —I. In embodiments, R²⁹ isindependently unsubstituted methyl. In embodiments, R²⁹ is independentlyunsubstituted ethyl.

R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —CH₂X³⁰, —OCX³⁰ ₃, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³¹-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³¹-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³¹-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³¹-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³¹-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R³¹-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³⁰ is independentlyoxo,halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —CH₂X³⁰, —OCX³⁰ ₃, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³⁰ is independently —F, —Cl, —Br, or —I. In embodiments, R³⁰ isindependently unsubstituted methyl. In embodiments, R³⁰ is independentlyunsubstituted ethyl.

R³¹ is independently oxo,

halogen, —CX³¹ ₃, —CHX³¹ ₂, —CH₂X³¹, —OCX³¹ ₃, —OCH₂X³¹, —OCHX³¹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³¹ is independently —F, —Cl, —Br, or —I. In embodiments, R³¹ isindependently unsubstituted methyl. In embodiments, R³¹ is independentlyunsubstituted ethyl.

In embodiments, R^(4A) is independently hydrogen. In embodiments, R^(4A)is independently —CX^(4A) ₃. In embodiments, R^(4A) is independently—CHX^(4A) ₂. In embodiments, R^(4A) is independently —CH₂X^(4A). Inembodiments, R^(4A) is independently —CN. In embodiments, R^(4A) isindependently —COOH. In embodiments, R^(4A) is independently —CONH₂. Inembodiments, X^(4A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(4A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(4A) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(4A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(4A) is independentlyunsubstituted methyl. In embodiments, R^(4A) is independentlyunsubstituted ethyl. In embodiments, R^(4A) is independentlyunsubstituted propyl. In embodiments, R^(4A) is independentlyunsubstituted isopropyl. In embodiments, R^(4A) is independentlyunsubstituted tert-butyl. In embodiments, R^(4A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(4A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(4A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(4A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(4A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(4A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(4A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(4A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(4A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(4A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(4A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(4A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(4A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(4A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(4A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(4A) is independently

hydrogen, —CX^(4A) ₃, —CHX^(4A) ₂, —CH₂X^(4A), —CN, —COOH, —CONH₂,R^(29A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(29A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(29A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(29A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(29A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(29A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4A) is independently hydrogen, —CX^(4A) ₃, —CHX^(4A) ₂, —CH₂X^(4A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(4A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(4A) is independently hydrogen. In embodiments, R^(4A) isindependently unsubstituted methyl. In embodiments, R^(4A) isindependently unsubstituted ethyl.

In embodiments, R^(4A) and R^(4B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(29A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(29A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(29A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(4A)and R^(4B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(29A) is independently oxo,

halogen, —CX^(29A) ₃, —CHX^(29A) ₂, —CH₂X^(29A), —OCX^(29A) ₃,—OCH₂X^(29A), —OCHX^(29A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(30A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(30A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(30A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(30A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(30A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(30A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(29A) isindependently oxo,halogen, —CX^(29A) ₃, —CHX^(29A) ₂, —CH₂X^(29A), —OCX^(29A) ₃,—OCH₂X^(29A), —OCHX^(29A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(29A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(29A) is independently unsubstituted methyl. Inembodiments, R^(29A) is independently unsubstituted ethyl.

R^(30A) is independently oxo,

halogen, —CX^(30A) ₃, —CHX^(30A) ₂, —CH₂X^(30A), —OCX^(30A) ₃,—OCH₂X^(30A), —OCHX^(30A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(31A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(31A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(31A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(31A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(31A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(31A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(30A) isindependently oxo,halogen, —CX^(30A) ₃, —CHX^(30A) ₂, —CH₂X^(30A), —OCX^(30A) ₃,—OCH₂X^(30A), —OCHX^(30A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(30A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(30A) is independently unsubstituted methyl. Inembodiments, R^(30A) is independently unsubstituted ethyl.

R^(31A) is independently oxo,

halogen, —CX^(31A) ₃, —CHX^(31A) ₂, —CH₂X^(31A), —OCX^(31A) ₃,—OCH₂X^(31A), —OCHX^(31A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(31A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(31A) is independently unsubstituted methyl. Inembodiments, R^(31A) is independently unsubstituted ethyl.

In embodiments, R^(4B) is independently hydrogen. In embodiments, R^(4B)is independently —CX^(4B) ₃. In embodiments, R^(4B) is independently—CHX^(4B) ₂. In embodiments, R^(4B) is independently —CH₂X^(4B). Inembodiments, R^(4B) is independently —CN. In embodiments, R^(4B) isindependently —COOH. In embodiments, R^(4B) is independently —CONH₂. Inembodiments, X^(4B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(4B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(4B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(4B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(4B) is independentlyunsubstituted methyl. In embodiments, R^(4B) is independentlyunsubstituted ethyl. In embodiments, R^(4B) is independentlyunsubstituted propyl. In embodiments, R^(4B) is independentlyunsubstituted isopropyl. In embodiments, R^(4B) is independentlyunsubstituted tert-butyl. In embodiments, R^(4B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(4B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(4B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(4B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(4B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(4B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(4B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(4B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(4B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(4B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(4B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(4B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(4B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(4B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(4B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(4A) and R^(4B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(4A)and R^(4B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(4A) and R^(4B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(4A) and R^(4B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(4A) and R^(4B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(4B) is independently

hydrogen, —CX^(4B) ₃, —CHX^(4B) ₂, —CH₂X^(4B), —CN, —COOH, —CONH₂,R^(29B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(29B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(29B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(29B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(29B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(29B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4B) is independently hydrogen, —CX^(4B) ₃, —CHX^(4B) ₂, —CH₂X^(4B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(4B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(4B) is independently hydrogen. In embodiments, R^(4B) isindependently unsubstituted methyl. In embodiments, R^(4B) isindependently unsubstituted ethyl.

In embodiments, R^(4A) and R^(4B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(29B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(29B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(29B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(4A)and R^(4B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(29B) is independently oxo,

halogen, —CX^(29B) ₃, —CHX^(29B) ₂, —CH₂X^(29B), —OCX^(29B) ₃,—OCH₂X^(29B), —OCHX^(29B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(30B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(30B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(30B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(30B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(30B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(30B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(29B) isindependently oxo,halogen, —CX^(29B) ₃, —CHX^(29B) ₂, —CH₂X^(29B), —OCX^(29B) ₃,—OCH₂X^(29B), —OCHX^(29B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(29B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(29B) is independently unsubstituted methyl. Inembodiments, R^(29B) is independently unsubstituted ethyl.

R^(30B) is independently oxo,

halogen, —CX^(30B) ₃, —CHX^(30B) ₂, —CH₂X^(30B), —OCX^(30B) ₃,—OCH₂X^(30B), —OCHX^(30B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(31B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(31B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(31B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(31B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(31B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(31B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(30B) isindependently oxo,halogen, —CX^(30B) ₃, —CHX^(30B) ₂, —CH₂X^(30B), —OCX^(30B) ₃,—OCH₂X^(30B), —OCHX^(30B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —OMB, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(30B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(30B) is independently unsubstituted methyl. Inembodiments, R^(30B) is independently unsubstituted ethyl.

R^(31B) is independently oxo,

halogen, —CX^(31B) ₃, —CHX^(31B) ₂, —CH₂X^(31B), —OCX^(31B) ₃,—OCH₂X^(31B), —OCHX^(31B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁—C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(31B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(31B) is independently unsubstituted methyl. Inembodiments, R^(31B) is independently unsubstituted ethyl.

In embodiments, R⁴ is hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, orunsubstituted C₁-C₂ alkyl. In embodiments, R⁴ is hydrogen.

In embodiments, L is independently a bond. In embodiments, L isindependently —N(R⁵)—.

In embodiments, R⁵ is independently hydrogen. In embodiments, R⁵ isindependently —CX⁵ ₃. In embodiments, R⁵ is independently —CHX⁵ ₂. Inembodiments, R⁵ is independently-CH₂X⁵. In embodiments, R⁵ isindependently-C(O)R^(5A). In embodiments, R⁵ is independently—C(O)OR^(5A). In embodiments, R⁵ is independently —C(O)NR^(5A)R^(5B). Inembodiments, R⁵ is independently —COOH. In embodiments, R⁵ isindependently —CONH₂. In embodiments, R⁵ is independently —CF₃. Inembodiments, R⁵ is independently —CHF₂. In embodiments, R⁵ isindependently —CH₂F. In embodiments, R⁵ is independently —CH₃. Inembodiments, R⁵ is independently —CH₂CH₃. In embodiments, R⁵ isindependently —CH₂CH₂CH₃. In embodiments, R⁵ is independently —CH(CH₃)₂.In embodiments, R⁵ is independently —C(CH₃)₃. In embodiments, R⁵ isindependently unsubstituted methyl. In embodiments, R⁵ is independentlyunsubstituted ethyl. In embodiments, R⁵ is independently unsubstitutedpropyl. In embodiments, R⁵ is independently unsubstituted isopropyl. Inembodiments, R⁵ is independently unsubstituted n-propyl. In embodiments,R⁵ is independently unsubstituted butyl. In embodiments, R⁵ isindependently unsubstituted n-butyl. In embodiments, R⁵ is independentlyunsubstituted t-butyl. In embodiments, R⁵ is independently unsubstitutediso-butyl. In embodiments, R⁵ is independently unsubstituted C₁-C₈alkyl. In embodiments, R⁵ is independently halo-substituted methyl. Inembodiments, R⁵ is independently halo-substituted ethyl. In embodiments,R⁵ is independently halo-substituted isopropyl. In embodiments, R⁵ isindependently halo-substituted n-propyl. In embodiments, R⁵ isindependently halo-substituted n-butyl. In embodiments, R⁵ isindependently halo-substituted t-butyl. In embodiments, R⁵ isindependently halo-substituted C₁-C₈ alkyl.

In embodiments, R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,—C(O)R^(5A), —C(O)—OR^(5A), —C(O)NR^(5A)R^(5B), substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁵ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁵ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R⁵ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁵ is independentlyunsubstituted methyl. In embodiments, R⁵ is independently unsubstitutedethyl. In embodiments, R⁵ is independently unsubstituted propyl. Inembodiments, R⁵ is independently unsubstituted isopropyl. Inembodiments, R⁵ is independently unsubstituted tert-butyl. Inembodiments, R⁵ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R⁵ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁵ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R⁵ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁵ isindependently substituted cycloalkyl (e.g., C₃-C₅, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁵ is independently unsubstituted cycloalkyl(e.g., C₃-C₅, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁵ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R⁵ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R⁵ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁵ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁵ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁵is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R⁵ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁵ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁵ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,—C(O)R^(5A), —C(O)—OR^(5A), —C(O)NR^(5A)R^(5B), R³²-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R³²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R³²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), R³²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R³²-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R³²-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,—C(O)—OH, —C(O)NH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X⁵ is independently —F, —Cl, —Br, or —I.

R³² is independently oxo,

halogen, —CX³² ₃, —CHX³² ₂, —CH₂X³², —OCX³² ₃, —OCH₂X³², —OCHX³² ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³³-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³³-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R³³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³² is independentlyoxo,halogen, —CX³² ₃, —CHX³² ₂, —CH₂X³², —OCX³² ₃, —OCH₂X³², —OCHX³² ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³² is independently —F, —Cl, —Br, or —I. In embodiments, R³² isindependently unsubstituted methyl. In embodiments, R³² is independentlyunsubstituted ethyl.

R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —CH₂X³³, —OCX³³ ₃, —OCH₂X³³, —OCHX³³ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³⁴-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁴-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³⁴-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R³⁴-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³³ is independentlyoxo,halogen, —CX³³ ₃, —CHX³³ ₂, —CH₂X³³, —OCX³³ ₃, —OCH₂X³³, —OCHX³³ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂ NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) MB, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³³ is independently —F, —Cl, —Br, or —I. In embodiments, R³³ isindependently unsubstituted methyl. In embodiments, R³³ is independentlyunsubstituted ethyl.

R³⁴ is independently oxo,

halogen, —CX³⁴ ₃, —CHX³⁴ ₂, —CH₂X³⁴, —OCX³⁴ ₃, —OCH₂X³⁴, —OCHX³⁴ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—OMB, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁—C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X³⁴ is independently —F, —Cl, —Br, or—I. In embodiments, R³⁴ is independently unsubstituted methyl. Inembodiments, R³⁴ is independently unsubstituted ethyl.

In embodiments, R^(5A) is independently hydrogen. In embodiments, R^(5A)is independently —CX^(5A) ₃. In embodiments, R^(5A) is independently—CHX^(5A) ₂. In embodiments, R^(5A) is independently —CH₂X^(5A). Inembodiments, R^(5A) is independently —CN. In embodiments, R^(5A) isindependently —COOH. In embodiments, R^(5A) is independently —CONH₂. Inembodiments, X^(5A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(5A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(5A) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(5A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(5A) is independentlyunsubstituted methyl. In embodiments, R^(5A) is independentlyunsubstituted ethyl. In embodiments, R^(5A) is independentlyunsubstituted propyl. In embodiments, R^(5A) is independentlyunsubstituted isopropyl. In embodiments, R^(5A) is independentlyunsubstituted tert-butyl. In embodiments, R^(5A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(5A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(5A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(5A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(5A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(5A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(5A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(5A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(5A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(5A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(5A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(5A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(5A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(5A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(5A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(5A) is independently

hydrogen, —CX^(5A) ₃, —CHX^(5A) ₂, —CH₂X^(5A), —CN, —COOH, —CONH₂,R^(32A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(32A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(32A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(32A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(32A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(32A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(5A) is independently hydrogen, —CX^(5A) ₃, —CHX^(5A) ₂, —CH₂X^(5A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(5A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(5A) is independently hydrogen. In embodiments, R^(5A) isindependently unsubstituted methyl. In embodiments, R^(5A) isindependently unsubstituted ethyl.

In embodiments, R^(5A) and R^(5B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(32A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(32A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(5A) and R^(5B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(5A) and R^(5B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(32A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(5A)and R^(5B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(32A) is independently oxo,

halogen, —CX^(32A) ₃, —CHX^(32A) ₂, —CH₂X^(32A), —OCX^(32A) ₃,—OCH₂X^(32A), —OCHX^(32A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(33A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(33A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(33A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(33A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(33A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(33A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(32A) isindependently oxo,halogen, —CX^(32A) ₃, —CHX^(32A) ₂, —CH₂X^(32A), —OCX^(32A) ₃,—OCH₂X^(32A), —OCHX^(32A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(32A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(32A) is independently unsubstituted methyl. Inembodiments, R^(32A) is independently unsubstituted ethyl.

R^(33A) is independently oxo,

halogen, —CX^(33A) ₃, —CHX^(33A) ₂, —CH₂X^(33A), —OCX^(33A) ₃,—OCH₂X^(33A), —OCHX^(33A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(34A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(34A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(34A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(34A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(34A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(34A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(33A) isindependently oxo,halogen, —CX^(33A) ₃, —CHX^(33A) ₂, —CH₂X^(33A), —OCX^(33A) ₃,—OCH₂X^(33A), —OCHX^(33A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(33A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(33A) is independently unsubstituted methyl. Inembodiments, R^(33A) is independently unsubstituted ethyl.

R^(34A) is independently oxo,

halogen, —CX^(34A) ₃, —CHX^(34A) ₂, —CH₂X^(34A), —OCX^(34A) ₃,—OCH₂X^(34A), —OCHX^(34A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(34A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(34A) is independently unsubstituted methyl. Inembodiments, R^(34A) is independently unsubstituted ethyl.

In embodiments, R^(5B) is independently hydrogen. In embodiments, R^(5B)is independently —CX^(5B) ₃. In embodiments, R^(5B) is independently—CHX^(5B) ₂. In embodiments, R^(5B) is independently —CH₂X^(5B). Inembodiments, R^(5B) is independently —CN. In embodiments, R^(5B) isindependently —COOH. In embodiments, R^(5B) is independently —CONH₂. Inembodiments, X^(5B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(5B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(5B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(5B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(5B) is independentlyunsubstituted methyl. In embodiments, R^(5B) is independentlyunsubstituted ethyl. In embodiments, R^(5B) is independentlyunsubstituted propyl. In embodiments, R^(5B) is independentlyunsubstituted isopropyl. In embodiments, R^(5B) is independentlyunsubstituted tert-butyl. In embodiments, R^(5B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(5B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(5B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(5B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(5B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(5B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(5B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(5B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(5B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(5B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(5B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(5B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(5B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(5B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(5B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(5A) and R^(5B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(5A)and R^(5B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(5A) and R^(5B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(5A) and R^(5B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(5A) and R^(5B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(5A) and R^(5B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(5B) is independently

hydrogen, —CX^(5B) ₃, —CHX^(5B) ₂, —CH₂X^(5B), —CN, —COOH, —CONH₂,R^(32B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(32B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(32B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(32B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(32B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(32B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(5B) is independently hydrogen, —CX^(5B) ₃, —CHX^(5B) ₂, —CH₂X^(5B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(5B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(5B) is independently hydrogen. In embodiments, R^(5B) isindependently unsubstituted methyl. In embodiments, R^(5B) isindependently unsubstituted ethyl.

In embodiments, R^(5A) and R^(5B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(32B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(32B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(5A) and R^(5B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(5A) and R^(5B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(32B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(5A)and R^(5B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(32B) is independently oxo,

halogen, —CX^(32B) ₃, —CHX^(32B) ₂, —CH₂X^(32B), —OCX^(32B) ₃,—OCH₂X^(32B), —OCHX^(32B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(33B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(33B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(33B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(33B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(33B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(33B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(32B) isindependently oxo,halogen, —CX^(32B) ₃, —CHX^(32B) ₂, —CH₂X^(32B), —OCX^(32B) ₃,—OCH₂X^(32B), —OCHX^(32B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(32B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(32B) is independently unsubstituted methyl. Inembodiments, R^(32B) is independently unsubstituted ethyl.

R^(33B) is independently oxo,

halogen, —CX³³—CHX^(33B) ₂, —CH₂X^(33B), —OCX^(33B) ₃, —OCH₂X^(33B),—OCHX^(33B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, R^(34B)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(34B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), R^(34B)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(34B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R^(34B)-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or R^(34B)-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R^(33B) is independently oxo,halogen, —CX^(33B) ₃, —CHX^(33B) ₂, —CH₂X^(33B), —OCX^(33B) ₃,—OCH₂X^(33B), —OCHX^(33B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(33B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(33B) is independently unsubstituted methyl. Inembodiments, R^(33B) is independently unsubstituted ethyl.

R^(34B) is independently oxo,

halogen, —CX^(34B) ₃, —CHX^(34B) ₂, —CH₂X^(34B), —OCX^(34B) ₃,—OCH₂X^(34B), —OCHX^(34B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(34B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(34B) is independently unsubstituted methyl. Inembodiments, R^(34B) is independently unsubstituted ethyl.

In embodiments, R⁵ is hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, orunsubstituted C₁-C₂ alkyl. In embodiments, R⁵ is hydrogen.

In embodiments, R⁶ is independently hydrogen. In embodiments, R⁶ isindependently —CX⁶ ₃. In embodiments, R⁶ is independently —CHX⁶ ₂. Inembodiments, R⁶ is independently —CH₂X⁶. In embodiments, R⁶ isindependently —C(O)R^(6A). In embodiments, R⁶ is independently—C(O)OR^(6A). In embodiments, R⁶ is independently —C(O)NR^(6A)R^(6B). Inembodiments, R⁶ is independently —COOH. In embodiments, R⁶ isindependently —CONH₂. In embodiments, R⁶ is independently-CF₃. Inembodiments, R⁶ is independently-CHF₂. In embodiments, R⁶ isindependently —CH₂F. In embodiments, R⁶ is independently —CH₃. Inembodiments, R⁶ is independently —CH₂CH₃. In embodiments, R⁶ isindependently —CH₂CH₂CH₃. In embodiments, R⁶ is independently —CH(CH₃)₂.In embodiments, R⁶ is independently —C(CH₃)₃. In embodiments, R⁶ isindependently unsubstituted methyl. In embodiments, R⁶ is independentlyunsubstituted ethyl. In embodiments, R⁶ is independently unsubstitutedpropyl. In embodiments, R⁶ is independently unsubstituted isopropyl. Inembodiments, R⁶ is independently unsubstituted n-propyl. In embodiments,R⁶ is independently unsubstituted butyl. In embodiments, R⁶ isindependently unsubstituted n-butyl. In embodiments, R⁶ is independentlyunsubstituted t-butyl. In embodiments, R⁶ is independently unsubstitutediso-butyl. In embodiments, R⁶ is independently unsubstituted C₁-C₈alkyl. In embodiments, R⁶ is independently halo-substituted methyl. Inembodiments, R⁶ is independently halo-substituted ethyl. In embodiments,R⁶ is independently halo-substituted isopropyl. In embodiments, R⁶ isindependently halo-substituted n-propyl. In embodiments, R⁶ isindependently halo-substituted n-butyl. In embodiments, R⁶ isindependently halo-substituted t-butyl. In embodiments, R⁶ isindependently halo-substituted C₁-C₈ alkyl.

In embodiments, R⁶ is independently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,—C(O)R^(6A), —C(O)—OR^(6A), —C(O)NR^(6A)R^(6B), substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁶ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁶ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R⁶ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁶ is independentlyunsubstituted methyl. In embodiments, R⁶ is independently unsubstitutedethyl. In embodiments, R⁶ is independently unsubstituted propyl. Inembodiments, R⁶ is independently unsubstituted isopropyl. Inembodiments, R⁶ is independently unsubstituted tert-butyl. Inembodiments, R⁶ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R⁶ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁶ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R⁶ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁶ isindependently substituted cycloalkyl (e.g., C₃-C₅, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁶ is independently unsubstituted cycloalkyl(e.g., C₃-C₅, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁶ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R⁶ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R⁶ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁶ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁶ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁶is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R⁶ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁶ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁶ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R⁶ is independently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,—C(O)R^(6A), —C(O)—OR^(6A), —C(O)NR^(6A)R^(6B), R³⁵-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R³⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R³⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), R³⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R³⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀,or phenyl), or R³⁵-substituted or unsubstituted heteroaryl (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R⁶ is independently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,—C(O)—OH, —C(O)NH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X⁶ is independently —F, —Cl, —Br, or —I.

R³⁵ is independently oxo,

halogen, —CX³⁵ ₃, —CHX³⁵ ₂, —CH₂X³⁵, —OCX³⁵ ₃, —OCH₂X³⁵, —OCHX³⁵ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³⁶-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³⁶-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³⁶-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R³⁶-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³⁵ is independentlyoxo,halogen, —CX³⁵ ₃, —CHX³⁵ ₂, —CH₂X³⁵, —OCX³⁵ ₃, —OCH₂X³⁵, —OCHX³⁵ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³⁵ is independently —F, —Cl, —Br, or —I. In embodiments, R³⁵ isindependently unsubstituted methyl. In embodiments, R³⁵ is independentlyunsubstituted ethyl.

R³⁶ is independently oxo,

halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —CH₂X³⁶, —OCX³⁶ ₃, —OCH₂X³⁶, —OCHX³⁶ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³⁷-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³⁷-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁷-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³⁷-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R³⁷-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³⁶ is independentlyoxo,halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —CH₂X³⁶, —OCX³⁶ ₃, —OCH₂X³⁶, —OCHX³⁶ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³⁶ is independently —F, —Cl, —Br, or —I. In embodiments, R³⁶ isindependently unsubstituted methyl. In embodiments, R³⁶ is independentlyunsubstituted ethyl.

R³⁷ is independently oxo,

halogen, —CX³⁷ ₃, —CHX³⁷ ₂, —CH₂X³⁷, —OCX³⁷ ₃, —OCH₂X³⁷, —OCHX³⁷ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³⁷ is independently —F, —Cl, —Br, or —I. In embodiments, R³⁷ isindependently unsubstituted methyl. In embodiments, R³⁷ is independentlyunsubstituted ethyl.

In embodiments, R^(6A) is independently hydrogen. In embodiments, R^(6A)is independently —CX^(6A) ₃. In embodiments, R^(6A) is independently—CHX^(6A) ₂. In embodiments, R^(6A) is independently —CH₂X^(6A). Inembodiments, R^(6A) is independently —CN. In embodiments, R^(6A) isindependently —COOH. In embodiments, R^(6A) is independently —CONH₂. Inembodiments, X^(6A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(6A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(6A) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(6A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(6A) is independentlyunsubstituted methyl. In embodiments, R^(6A) is independentlyunsubstituted ethyl. In embodiments, R^(6A) is independentlyunsubstituted propyl. In embodiments, R^(6A) is independentlyunsubstituted isopropyl. In embodiments, R^(6A) is independentlyunsubstituted tert-butyl. In embodiments, R^(6A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(6A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(6A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(6A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(6A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(6A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(6A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(6A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(6A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(6A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(6A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(6A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(6A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(6A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(6A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(6A) is independently

hydrogen, —CX^(6A) ₃, —CHX^(6A) ₂, —CH₂X^(6A), —CN, —COOH, —CONH₂,R^(35A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(35A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(35A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(35A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(35A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(35A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(6A) is independently hydrogen, —CX^(6A) ₃, —CHX^(6A) ₂, —CH₂X^(6A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(6A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(6A) is independently hydrogen. In embodiments, R^(6A) isindependently unsubstituted methyl. In embodiments, R^(6A) isindependently unsubstituted ethyl.

In embodiments, R^(6A) and R^(6B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(35A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(35A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(6A) and R^(6B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(6A) and R^(6B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(35A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(6A)and R^(6B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(35A) is independently oxo,

halogen, —CX^(35A) ₃, —CHX^(35A) ₂, —CH₂X^(35A), —OCX^(35A) ₃,—OCH₂X^(35A), —OCHX^(35A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(36A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(36A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(36A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(36A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(36A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(36A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(35A) isindependently oxo,halogen, —CX^(35A) ₃, —CHX^(35A) ₂, —CH₂X^(35A), —OCX^(35A) ₃,—OCH₂X^(35A), —OCHX^(35A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(35A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(35A) is independently unsubstituted methyl. Inembodiments, R^(35A) is independently unsubstituted ethyl.

R^(36A) is independently oxo,

halogen, —CX^(36A) ₃, —CHX^(36A) ₂, —CH₂X^(36A), —OCX^(36A) ₃,—OCH₂X^(36A), —OCHX^(36A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(37A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(37A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(37A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(37A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(37A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(37A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(36A) isindependently oxo,halogen, —CX^(36A) ₃, —CHX^(36A) ₂, —CH₂X^(36A), —OCX^(36A) ₃,—OCH₂X^(36A), —OCHX^(36A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(36A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(36A) is independently unsubstituted methyl. Inembodiments, R^(36A) is independently unsubstituted ethyl.

R^(37A) is independently oxo,

halogen, —CX^(37A) ₃, —CHX^(37A) ₂, —CH₂X^(37A), —OCX^(37A) ₃,—OCH₂X^(37A), —OCHX^(37A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(37A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(37A) is independently unsubstituted methyl. Inembodiments, R^(37A) is independently unsubstituted ethyl.

In embodiments, R^(6B) is independently hydrogen. In embodiments, R^(6B)is independently —CX^(6B) ₃. In embodiments, R^(6B) is independently—CHX^(6B) ₂. In embodiments, R^(6B) is independently —CH₂X^(6B). Inembodiments, R^(6B) is independently —CN. In embodiments, R^(6B) isindependently —COOH. In embodiments, R^(6B) is independently —CONH₂. Inembodiments, X^(6B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(6B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(6B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(6B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁—C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(6B) is independentlyunsubstituted methyl. In embodiments, R^(6B) is independentlyunsubstituted ethyl. In embodiments, R^(6B) is independentlyunsubstituted propyl. In embodiments, R^(6B) is independentlyunsubstituted isopropyl. In embodiments, R^(6B) is independentlyunsubstituted tert-butyl. In embodiments, R^(6B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(6B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(6B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(6B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(6B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(6B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(6B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(6B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(6B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(6B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(6B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(6B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(6B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(6B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(6B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(6A) and R^(6B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(6A)and R^(6B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(6A) and R^(6B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(6A) and R^(6B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(6A) and R^(6B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(6A) and R^(6B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(6B) is independently

hydrogen, —CX^(6B) ₃, —CHX^(6B) ₂, —CH₂X^(6B), —CN, —COOH, —CONH₂,R^(35B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(35B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(35B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(35B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(35B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(35B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(6B) is independently hydrogen, —CX^(6B) ₃, —CHX^(6B) ₂, —CH₂X^(6B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(6B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(6B) is independently hydrogen. In embodiments, R^(6B) isindependently unsubstituted methyl. In embodiments, R^(6B) isindependently unsubstituted ethyl.

In embodiments, R^(6A) and R^(6B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(35B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(35B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(6A) and R^(6B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(6A) and R^(6B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(35B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(6A)and R^(6B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(35B) is independently oxo,

halogen, —CX^(35B) ₃, —CHX^(35B) ₂, —CH₂X^(35B), —OCX^(35B) ₃,—OCH₂X^(35B), —OCHX^(35B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(36B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(36B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(36B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(36B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(36B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(36B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(35B) isindependently oxo,halogen, —CX^(35B) ₃, —CHX^(35B) ₂, —CH₂X^(35B), —OCX^(35B) ₃,—OCH₂X^(35B), —OCHX^(35B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(35B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(35B) is independently unsubstituted methyl. Inembodiments, R^(35B) is independently unsubstituted ethyl.

R^(36B) is independently oxo,

halogen, —CX^(36B) ₃, —CHX^(36B) ₂, —CH₂X^(36B), —OCX^(36B) ₃,—OCH₂X^(36B), —OCHX^(36B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(37B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(37B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(37B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(37B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(37B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(37B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(36B) isindependently oxo,halogen, —CX^(36B) ₃, —CHX^(36B) ₂, —CH₂X^(36B), —OCX^(36B) ₃,—OCH₂X^(36B), —OCHX^(36B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(36B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(36B) is independently unsubstituted methyl. Inembodiments, R^(36B) is independently unsubstituted ethyl.

R^(37B) is independently oxo,

halogen, —CX^(37B) ₃, —CHX^(37B) ₂, —CH₂X^(37B), —OCX^(37B) ₃,—OCH₂X^(37B), —OCHX^(37B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(37B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(37B) is independently unsubstituted methyl. Inembodiments, R^(37B) is independently unsubstituted ethyl.

In embodiments, R⁶ is hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, orunsubstituted C₁-C₂ alkyl. In embodiments, R⁶ is hydrogen.

In embodiments, R⁷ is independently hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂,—CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —SO_(n7)R^(7A),—SO_(v7)NR^(7A)R^(7B), —NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B),—C(O)R^(7A), —C(O)OR^(7A), —C(O)NR^(7A)R^(7B), —OR^(7A),—NR^(7A)SO₂R^(7B), —NR^(7A)C(O)R^(7B), —NR^(7A)C(O)OR^(7B),—NR^(7A)OR^(7B), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁷ is independently hydrogen. In embodiments, R⁷ isindependently —CX⁷ ₃. In embodiments, R⁷ is independently —CHX⁷ ₂. Inembodiments, R⁷ is independently —CH₂X⁷. In embodiments, R⁷ isindependently —OCX⁷ ₃. In embodiments, R⁷ is independently —OCH₂X⁷. Inembodiments, R⁷ is independently —OCHX⁷ ₂. In embodiments, R⁷ isindependently —CN. In embodiments, R⁷ is independently —C(O)R^(7A). Inembodiments, R⁷ is independently-C(O)OR^(7A). In embodiments, R⁷ isindependently-C(O)NR^(7A)R^(7B). In embodiments, R⁷ is independently—OR^(7A). In embodiments, R⁷ is independently —OH. In embodiments, R⁷ isindependently —COOH. In embodiments, R⁷ is independently —CONH₂. Inembodiments, R⁷ is independently —CF₃. In embodiments, R⁷ isindependently —CHF₂. In embodiments, R⁷ is independently —CH₂F. Inembodiments, R⁷ is independently —OCF₃. In embodiments, R⁷ isindependently-OCH₂F. In embodiments, R⁷ is independently-OCHF₂. Inembodiments, R⁷ is independently —OCH₃. In embodiments, R⁷ isindependently —OCH₂CH₃. In embodiments, R⁷ is independently —OCH₂CH₂CH₃.In embodiments, R⁷ is independently —OCH(CH₃)₂. In embodiments, R⁷ isindependently —OC(CH₃)₃. In embodiments, R⁷ is independently —CH₃. Inembodiments, R⁷ is independently —CH₂CH₃. In embodiments, R⁷ isindependently —CH₂CH₂CH₃. In embodiments, R⁷ is independently —CH(CH₃)₂.In embodiments, R⁷ is independently —C(CH₃)₃. In embodiments, R⁷ isindependently unsubstituted methyl. In embodiments, R⁷ is independentlyunsubstituted ethyl. In embodiments, R⁷ is independently unsubstitutedpropyl. In embodiments, R⁷ is independently unsubstituted isopropyl. Inembodiments, R⁷ is independently unsubstituted n-propyl. In embodiments,R⁷ is independently unsubstituted butyl. In embodiments, R⁷ isindependently unsubstituted n-butyl. In embodiments, R⁷ is independentlyunsubstituted t-butyl. In embodiments, R⁷ is independently unsubstitutediso-butyl. In embodiments, R⁷ is independently unsubstituted C₁-C₈alkyl. In embodiments, R⁷ is independently halo-substituted methyl. Inembodiments, R⁷ is independently halo-substituted ethyl. In embodiments,R⁷ is independently halo-substituted isopropyl. In embodiments, R⁷ isindependently halo-substituted n-propyl. In embodiments, R⁷ isindependently halo-substituted n-butyl. In embodiments, R⁷ isindependently halo-substituted t-butyl. In embodiments, R⁷ isindependently halo-substituted C₁-C₈ alkyl. In embodiments, R⁷ isindependently —N₃.

In embodiments, R⁷ is independently hydrogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷,—OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —C(O)R^(7A), —C(O)OR^(7A),—C(O)NR^(7A)R^(7B), —OR^(7A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R⁷ is independently hydrogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷,—OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —C(O)R^(7A), —C(O)—OR^(7A),—C(O)NR^(7A)R^(7B), —OR^(7A), substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R⁷ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁷ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R⁷ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁷ is independentlyunsubstituted methyl. In embodiments, R⁷ is independently unsubstitutedethyl. In embodiments, R⁷ is independently unsubstituted propyl. Inembodiments, R⁷ is independently unsubstituted isopropyl. Inembodiments, R⁷ is independently unsubstituted tert-butyl. Inembodiments, R⁷ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R⁷ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁷ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R⁷ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁷ isindependently substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁷ is independently unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁷ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R⁷ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R⁷ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁷ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁷ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁷is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R⁷ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁷ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁷ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R⁷ is independently hydrogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷,—OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —C(O)R^(7A), —C(O)—OR^(7A),—C(O)NR^(7A)R^(7B), —OR^(7A), R³⁸-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³⁸-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), R³⁸-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁸-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R³⁸-substitutedor unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR³⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁷is independently hydrogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷,—OCHX⁷ ₂, —CN, —C(O)—OH, —C(O)NH₂, —OH, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X⁷ is independently —F, —Cl, —Br, or —I.

R³⁸ is independently oxo,

halogen, —CX³⁸ ₃, —CHX³⁸ ₂, —CH₂X³⁸, —OCX³⁸ ₃, —OCH₂X³⁸, —OCHX³⁸ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R³⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R³⁹-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R³⁹-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁹-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R³⁹-substituted orunsubstituted aryl (e.g., C₆—C₁₂, C₆-C₁₀, or phenyl), or R³⁹-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³⁸ is independentlyoxo,halogen, —CX³⁸ ₃, —CHX³⁸ ₂, —CH₂X³⁸, —OCX³⁸ ₃, —OCH₂X³⁸, —OCHX³⁸ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³⁸ is independently —F, —Cl, —Br, or —I. In embodiments, R³⁸ isindependently unsubstituted methyl. In embodiments, R³⁸ is independentlyunsubstituted ethyl.

R³⁹ is independently oxo,

halogen, —CX³⁹ ₃, —CHX³⁹ ₂, —CH₂X³⁹, —OCX³⁹ ₃, —OCH₂X³⁹, —OCHX³⁹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R⁴⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R⁴⁰-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R⁴⁰-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R⁴⁰-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R³⁹ is independentlyoxo,halogen, —CX³⁹ ₃, —CHX³⁹ ₂, —CH₂X³⁹, —OCX³⁹ ₃, —OCH₂X³⁹, —OCHX³⁹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X³⁹ is independently —F, —Cl, —Br, or —I. In embodiments, R³⁹ isindependently unsubstituted methyl. In embodiments, R³⁹ is independentlyunsubstituted ethyl.

R⁴⁰ is independently oxo,

halogen, —CX⁴⁰ ₃, —CHX⁴⁰ ₂, —CH₂X⁴⁰, —OCX⁴⁰ ₃, —OCH₂X⁴⁰, —OCHX⁴⁰ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X⁴⁰ is independently —F, —Cl, —Br, or —I. In embodiments, R⁴⁰ isindependently unsubstituted methyl. In embodiments, R⁴⁰ is independentlyunsubstituted ethyl.

In embodiments, R^(7A) is independently hydrogen. In embodiments, R^(7A)is independently —CX^(7A) ₃. In embodiments, R^(7A) is independently—CHX^(7A) ₂. In embodiments, R^(7A) is independently —CH₂X^(7A). Inembodiments, R^(7A) is independently —CN. In embodiments, R^(7A) isindependently —COOH. In embodiments, R^(7A) is independently —CONH₂. Inembodiments, X^(7A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(7A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(7A) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(7A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(7A) is independentlyunsubstituted methyl. In embodiments, R^(7A) is independentlyunsubstituted ethyl. In embodiments, R^(7A) is independentlyunsubstituted propyl. In embodiments, R^(7A) is independentlyunsubstituted isopropyl. In embodiments, R^(7A) is independentlyunsubstituted tert-butyl. In embodiments, R^(7A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(7A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(7A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(7A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(7A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(7A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(7A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(7A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(7A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(7A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(7A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(7A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(7A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(7A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(7A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(7A) is independently

hydrogen, —CX^(7A) ₃, —CHX^(7A) ₂, —CH₂X^(7A), —CN, —COOH, —CONH₂,R^(38A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(38A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(38A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(38A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(38A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(38A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(7A) is independently hydrogen, —CX^(7A) ₃, —CHX^(7A) ₂, —CH₂X^(7A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(7A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(7A) is independently hydrogen. In embodiments, R^(7A) isindependently unsubstituted methyl. In embodiments, R^(7A) isindependently unsubstituted ethyl.

In embodiments, R^(7A) and R^(7B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(38A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(38A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(7A) and R^(7B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(7A) and R^(7B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(38A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(7A)and R^(7B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(38A) is independently oxo,

halogen, —CX^(38A) ₃, —CHX^(38A) ₂, —CH₂X^(38A), —OCX^(38A) ₃,—OCH₂X^(38A), —OCHX^(38A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(39A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(39A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(39A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(39A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(39A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(39A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(38A) isindependently oxo,halogen, —CX^(38A) ₃, —CHX^(38A) ₂, —CH₂X^(38A), —OCX^(38A) ₃,—OCH₂X^(38A), —OCHX^(38A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(38A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(38A) is independently unsubstituted methyl. Inembodiments, R^(38A) is independently unsubstituted ethyl.

R^(39A) is independently oxo,

halogen, —CX^(39A) ₃, —CHX^(39A) ₂, —CH₂X^(39A), —OCX^(39A) ₃,—OCH₂X^(39A), —OCHX^(39A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(40A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(40A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(40A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(40A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(40A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(40A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(39A) isindependently oxo,halogen, —CX^(39A) ₃, —CHX^(39A) ₂, —CH₂X^(39A), —OCX^(39A) ₃,—OCH₂X^(39A), —OCHX^(39A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(39A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(39A) is independently unsubstituted methyl. Inembodiments, R^(39A) is independently unsubstituted ethyl.

R^(40A) is independently oxo,

halogen, —CX^(40A) ₃, —CHX^(40A) ₂, —CH₂X^(40A), —OCX^(40A) ₃,—OCH₂X^(40A), —OCHX^(40A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(40A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(40A) is independently unsubstituted methyl. Inembodiments, R^(40A) is independently unsubstituted ethyl.

In embodiments, R^(7B) is independently hydrogen. In embodiments, R^(7B)is independently —CX^(7B) ₃. In embodiments, R^(7B) is independently—CHX^(7B) ₂. In embodiments, R^(7B) is independently —CH₂X^(7B). Inembodiments, R^(7B) is independently —CN. In embodiments, R^(7B) isindependently —COOH. In embodiments, R^(7B) is independently —CONH₂. Inembodiments, X^(7B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(7B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(7B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(7B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(7B) is independentlyunsubstituted methyl. In embodiments, R^(7B) is independentlyunsubstituted ethyl. In embodiments, R^(7B) is independentlyunsubstituted propyl. In embodiments, R^(7B) is independentlyunsubstituted isopropyl. In embodiments, R^(7B) is independentlyunsubstituted tert-butyl. In embodiments, R^(7B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(7B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(7B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(7B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(7B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(7B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(7B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(7B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(7B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(7B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(7B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(7B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(7B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(7B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(7B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(7A) and R^(7B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(7A)and R^(7B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(7A) and R^(7B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(7A) and R^(7B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(7A) and R^(7B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(7A) and R^(7B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(7B) is independently

hydrogen, —CX^(7B) ₃, —CHX^(7B) ₂, —CH₂X^(7B), —CN, —COOH, —CONH₂,R^(38B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(38B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(38B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(38B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(38B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(38B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(7B) is independently hydrogen, —CX^(7B) ₃, —CHX^(7B) ₂, —CH₂X^(7B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(7B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(7B) is independently hydrogen. In embodiments, R^(7B) isindependently unsubstituted methyl. In embodiments, R^(7B) isindependently unsubstituted ethyl.

In embodiments, R^(7A) and R^(7B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(38B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(38B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(7A) and R^(7B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(7A) and R^(7B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(38B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(7A)and R^(7B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(38B) is independently oxo,

halogen, —CX^(38B) ₃, —CHX^(38B) ₂, —CH₂X^(38B), —OCX^(38B) ₃,—OCH₂X^(38B), —OCHX^(38B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(39B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(39B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(39B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(39B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(39B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(39B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(38B) isindependently oxo,halogen, —CX^(38B) ₃, —CHX^(38B) ₂, —CH₂X^(38B), —OCX^(38B) ₃,—OCH₂X^(38B), —OCHX^(38B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(38B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(38B) is independently unsubstituted methyl. Inembodiments, R^(38B) is independently unsubstituted ethyl.

R^(39B) is independently oxo,

halogen, —CX^(39B) ₃, —CHX^(39B) ₂, —CH₂X^(39B), —OCX^(39B) ₃,—OCH₂X^(39B), —OCHX^(39B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(40B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(40B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(40B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(40B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(40B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(40B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(39B) isindependently oxo,halogen, —CX^(39B) ₃, —CHX^(39B) ₂, —CH₂X^(39B), —OCX^(39B) ₃,—OCH₂X^(39B), —OCHX^(39B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —OMB, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(39B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(39B) is independently unsubstituted methyl. Inembodiments, R^(39B) is independently unsubstituted ethyl.

R^(40B) is independently oxo,

halogen, —CX^(40B) ₃, —CHX^(40B) ₂, —CH₂X^(40B), —OCX^(40B) ₃,—OCH₂X^(40B), —OCHX^(40B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁—C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(40B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(40B) is independently unsubstituted methyl. Inembodiments, R^(40B) is independently unsubstituted ethyl.

In embodiments, R⁷ is hydrogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, orunsubstituted C₁-C₂ alkyl. In embodiments, R⁷ is hydrogen.

In embodiments, R⁸ is independently hydrogen, halogen, —CX⁸ ₃, —CHX⁸ ₂,—CH₂X⁸, —OCX⁸ ₃, —OCH₂X⁸, —OCHX⁸ ₂, —CN, —SO_(n8)R^(8A),—SO_(v8)NR^(8A)R^(8B), —NHC(O)NR^(8A)R^(8B), —N(O)_(m8), —NR^(8A)R^(8B),—C(O)R^(8A), —C(O)OR^(8A), —C(O)NR^(8A)R^(8B), —OR^(8A),—NR^(8A)SO₂R^(8B), —NR^(8A)C(O)R^(8B), —NR^(8A)C(O)OR^(8B),—NR^(8A)OR^(8B), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁸ is independently hydrogen. In embodiments, R⁸ isindependently —CX⁸ ₃. In embodiments, R⁸ is independently —CHX⁸ ₂. Inembodiments, R⁸ is independently —CH₂X⁸. In embodiments, R⁸ isindependently —OCX⁸ ₃. In embodiments, R⁸ is independently —OCH₂X⁸. Inembodiments, R⁸ is independently —OCHX⁸ ₂. In embodiments, R⁸ isindependently —CN. In embodiments, R⁸ is independently —C(O)R^(8A). Inembodiments, R⁸ is independently —C(O)OR^(8A). In embodiments, R⁸ isindependently —C(O)NR^(8A)R^(8B). In embodiments, R⁸ is independently—OR^(8A). In embodiments, R⁸ is independently —OH. In embodiments, R⁸ isindependently —COOH. In embodiments, R⁸ is independently —CONH₂. Inembodiments, R⁸ is independently —CF₃. In embodiments, R⁸ isindependently —CHF₂. In embodiments, R⁸ is independently —CH₂F. Inembodiments, R⁸ is independently —OCF₃. In embodiments, R⁸ isindependently —OCH₂F. In embodiments, R⁸ is independently —OCHF₂. Inembodiments, R⁸ is independently —OCH₃. In embodiments, R⁸ isindependently —OCH₂CH₃. In embodiments, R⁸ is independently —OCH₂CH₂CH₃.In embodiments, R⁸ is independently —OCH(CH₃)₂. In embodiments, R⁸ isindependently —OC(CH₃)₃. In embodiments, R⁸ is independently —CH₃. Inembodiments, R⁸ is independently —CH₂CH₃. In embodiments, R⁸ isindependently —CH₂CH₂CH₃. In embodiments, R⁸ is independently —CH(CH₃)₂.In embodiments, R⁸ is independently —C(CH₃)₃. In embodiments, R⁸ isindependently unsubstituted methyl. In embodiments, R⁸ is independentlyunsubstituted ethyl. In embodiments, R⁸ is independently unsubstitutedpropyl. In embodiments, R⁸ is independently unsubstituted isopropyl. Inembodiments, R⁸ is independently unsubstituted n-propyl. In embodiments,R⁸ is independently unsubstituted butyl. In embodiments, R⁸ isindependently unsubstituted n-butyl. In embodiments, R⁸ is independentlyunsubstituted t-butyl. In embodiments, R⁸ is independently unsubstitutediso-butyl. In embodiments, R⁸ is independently unsubstituted C₁-C₈alkyl. In embodiments, R⁸ is independently halo-substituted methyl. Inembodiments, R⁸ is independently halo-substituted ethyl. In embodiments,R⁸ is independently halo-substituted isopropyl. In embodiments, R⁸ isindependently halo-substituted n-propyl. In embodiments, R⁸ isindependently halo-substituted n-butyl. In embodiments, R⁸ isindependently halo-substituted t-butyl. In embodiments, R⁸ isindependently halo-substituted C₁-C₈ alkyl. In embodiments, R⁸ isindependently —N₃.

In embodiments, R⁸ is independently hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸,—OCX⁸ ₃, —OCH₂X⁸, —OCHX⁸ ₂, —CN, —C(O)R^(8A), —C(O)OR^(8A),—C(O)NR^(8A)R^(8B), —OR^(8A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R⁸ is independently hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸,—OCX⁸ ₃, —OCH₂X⁸, —OCHX⁸ ₂, —CN, —C(O)R^(8A), —C(O)—OR^(8A),—C(O)NR^(8A)R^(8B), —OR^(8A), substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R⁸ is independently substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁸ isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R⁸ is independently unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁸ is independentlyunsubstituted methyl. In embodiments, R⁸ is independently unsubstitutedethyl. In embodiments, R⁸ is independently unsubstituted propyl. Inembodiments, R⁸ is independently unsubstituted isopropyl. Inembodiments, R⁸ is independently unsubstituted tert-butyl. Inembodiments, R⁸ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R⁸ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁸ isindependently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R⁸ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁸ isindependently substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁸ is independently unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R⁸ isindependently substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, R⁸ is independently substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R⁸ isindependently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁸ is independently substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁸ is independentlysubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R⁸is independently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl).In embodiments, R⁸ is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁸ is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R⁸ is independently unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R⁸ is independently hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸,—OCX⁸ ₃, —OCH₂X⁸, —OCHX⁸ ₂, —CN, —C(O)R^(8A), —C(O)—OR^(8A),—C(O)NR^(8A)R^(8B), —OR^(8A), R⁴¹-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴¹-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), R⁴¹-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴¹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R⁴¹-substitutedor unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR⁴¹-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁸is independently hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, —OCX⁸ ₃, —OCH₂X⁸,—OCHX⁸ ₂, —CN, —C(O)—OH, —C(O)NH₂, —OH, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X⁸ is independently —F, —Cl, —Br, or —I.

R⁴¹ is independently oxo,

halogen, —CX⁴¹ ₃, —CHX⁴¹ ₂, —CH₂X⁴¹, —OCX⁴¹ ₃, —OCH₂X⁴¹, —OCHX⁴¹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R⁴²-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R⁴²-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R⁴²-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴²-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R⁴²-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R⁴²-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R⁴¹ is independentlyoxo,halogen, —CX⁴¹ ₃, —CHX⁴¹ ₂, —CH₂X⁴¹, —OCX⁴¹ ₃, —OCH₂X⁴¹, —OCHX⁴¹ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X⁴¹ is independently —F, —Cl, —Br, or —I. In embodiments, R⁴¹ isindependently unsubstituted methyl. In embodiments, R⁴¹ is independentlyunsubstituted ethyl.

R⁴² is independently oxo,

halogen, —CX⁴² ₃, —CHX⁴² ₂, —CH₂X⁴², —OCX⁴² ₃, —OCH₂X⁴², —OCHX⁴² ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, R⁴³-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R⁴³-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), R⁴³-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R⁴³-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R⁴³-substitutedor unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered). In embodiments, R⁴² is independentlyoxo,halogen, —CX⁴² ₃, —CHX⁴² ₂, —CH₂X⁴², —OCX⁴² ₃, —OCH₂X⁴², —OCHX⁴² ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X⁴² is independently —F, —Cl, —Br, or —I. In embodiments, R⁴² isindependently unsubstituted methyl. In embodiments, R⁴² is independentlyunsubstituted ethyl.

R⁴³ is independently oxo,

halogen, —CX⁴³ ₃, —CHX⁴³ ₂, —CH₂X⁴³, —OCX⁴³ ₃, —OCH₂X⁴³, —OCHX⁴³ ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X⁴³ is independently —F, —Cl, —Br, or —I. In embodiments, R⁴³ isindependently unsubstituted methyl. In embodiments, R⁴³ is independentlyunsubstituted ethyl.

In embodiments, R^(8A) is independently hydrogen. In embodiments, R^(8A)is independently —CX^(8A) ₃. In embodiments, R^(8A) is independently—CHX^(8A) ₂. In embodiments, R^(8A) is independently —CH₂X^(8A). Inembodiments, R^(8A) is independently —CN. In embodiments, R^(8A) isindependently —COOH. In embodiments, R^(8A) is independently —CONH₂. Inembodiments, X^(8A) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(8A) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(8A) isindependently substituted alkyl (e.g., C₁-C₈, C₁—C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(8A) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(8A) is independentlyunsubstituted methyl. In embodiments, R^(8A) is independentlyunsubstituted ethyl. In embodiments, R^(8A) is independentlyunsubstituted propyl. In embodiments, R^(8A) is independentlyunsubstituted isopropyl. In embodiments, R^(8A) is independentlyunsubstituted tert-butyl. In embodiments, R^(8A) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(8A) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(8A) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(8A) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(8A) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(8A) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(8A) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(8A) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(8A) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(8A)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(8A) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(8A) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(8A) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(8A) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(8A) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(8A) is independently

hydrogen, —CX^(8A) ₃, —CHX^(8A) ₂, —CH₂X^(8A), —CN, —COOH, —CONH₂,R^(41A)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(41A)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(41A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(41A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(41A)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(41A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(8A) is independently hydrogen, —CX^(8A) ₃, —CHX^(8A) ₂, —CH₂X^(8A),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(8A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(8A) is independently hydrogen. In embodiments, R^(8A) isindependently unsubstituted methyl. In embodiments, R^(8A) isindependently unsubstituted ethyl.

In embodiments, R^(8A) and R^(8B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(41A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(41A)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(8A) and R^(8B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(8A) and R^(8B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(41A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(8A)and R^(8B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(41A) is independently oxo,

halogen, —CX^(41A) ₃, —CHX^(41A) ₂, —CH₂X^(41A), —OCX^(41A) ₃,—OCH₂X^(41A), —OCHX^(41A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(42A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(42A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(42A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(42A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(42A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(42A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(41A) isindependently oxo,halogen, —CX^(41A) ₃, —CHX^(41A) ₂, —CH₂X^(41A), —OCX^(41A) ₃,—OCH₂X^(41A), —OCHX^(41A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(41A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(41A) is independently unsubstituted methyl. Inembodiments, R^(41A) is independently unsubstituted ethyl.

R^(42A) is independently oxo,

halogen, —CX^(42A) ₃, —CHX^(42A) ₂, —CH₂X^(42A), —OCX^(42A) ₃,—OCH₂X^(42A), —OCHX^(42A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(43A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(43A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(43A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(43A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(43A)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(43A)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(42A) isindependently oxo,halogen, —CX^(42A) ₃, —CHX^(42A) ₂, —CH₂X^(42A), —OCX^(42A) ₃,—OCH₂X^(42A), —OCHX^(42A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(42A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(42A) is independently unsubstituted methyl. Inembodiments, R^(42A) is independently unsubstituted ethyl.

R^(43A) is independently oxo,

halogen, —CX^(43A) ₃, —CHX^(43A) ₂, —CH₂X^(43A), —OCX^(43A) ₃,—OCH₂X^(43A), —OCHX^(43A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(43A) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(43A) is independently unsubstituted methyl. Inembodiments, R^(43A) is independently unsubstituted ethyl.

In embodiments, R^(8B) is independently hydrogen. In embodiments, R^(8B)is independently —CX^(8B) ₃. In embodiments, R^(8B) is independently—CHX^(8B) ₂. In embodiments, R^(8B) is independently —CH₂X^(8B). Inembodiments, R^(8B) is independently —CN. In embodiments, R^(8B) isindependently —COOH. In embodiments, R^(8B) is independently —CONH₂. Inembodiments, X^(8B) is independently —F, —Cl, —Br, or —I.

In embodiments, R^(8B) is independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(8B) isindependently substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).In embodiments, R^(8B) is independently unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R^(8B) is independentlyunsubstituted methyl. In embodiments, R^(8B) is independentlyunsubstituted ethyl. In embodiments, R^(8B) is independentlyunsubstituted propyl. In embodiments, R^(8B) is independentlyunsubstituted isopropyl. In embodiments, R^(8B) is independentlyunsubstituted tert-butyl. In embodiments, R^(8B) is independentlysubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R^(8B) is independently substituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, R^(8B) is independently unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R^(8B) isindependently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(8B) is independentlysubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R^(8B) is independently unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R^(8B) is independentlysubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(8B) is independently substituted heterocycloalkyl (e.g.,3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered). In embodiments, R^(8B) is independently unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(8B)is independently substituted or unsubstituted aryl (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl). In embodiments, R^(8B) is independently substitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). In embodiments, R^(8B) isindependently unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl). Inembodiments, R^(8B) is independently substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(8B) is independently substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(8B) is independentlyunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(8A) and R^(8B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(8A)and R^(8B) substituents bonded to the same nitrogen atom may be joinedto form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R^(8A) and R^(8B) substituents bonded to the same nitrogenatom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R^(8A) and R^(8B) substituents bonded to the samenitrogen atom may be joined to form a substituted or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(8A) and R^(8B) substituentsbonded to the same nitrogen atom may be joined to form a substitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). In embodiments, R^(8A) and R^(8B) substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(8B) is independently

hydrogen, —CX^(8B) ₃, —CHX^(8B) ₂, —CH₂X^(8B), —CN, —COOH, —CONH₂,R^(41B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(41B)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(41B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(41B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(41B)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(41B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(8B) is independently hydrogen, —CX^(8B) ₃, —CHX^(8B) ₂, —CH₂X^(8B),—CN, —COOH, —CONH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(8B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(8B) is independently hydrogen. In embodiments, R^(8B) isindependently unsubstituted methyl. In embodiments, R^(8B) isindependently unsubstituted ethyl.

In embodiments, R^(8A) and R^(8B) substituents bonded to the samenitrogen atom may optionally be joined to form a R^(41B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orR^(41B)-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(8A) and R^(8B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(8A) and R^(8B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(41B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R^(8A)and R^(8B) substituents bonded to the same nitrogen atom may optionallybe joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

R^(41B) is independently oxo,

halogen, —CX^(41B) ₃, —CHX^(41B) ₂, —CH₂X^(41B), —OCX^(41B) ₃,—OCH₂X^(41B), —OCHX^(41B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(42B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(42B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(42B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(42B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(42B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(42B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(41B) isindependently oxo,halogen, —CX^(41B) ₃, —CHX^(41B) ₂, —CH₂X^(41B), —OCX^(41B) ₃,—OCH₂X^(41B), —OCHX^(41B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(41B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(41B) is independently unsubstituted methyl. Inembodiments, R^(41B) is independently unsubstituted ethyl.

R^(42B) is independently oxo,

halogen, —CX^(42B) ₃, —CHX^(42B) ₂, —CH₂X^(42B), —OCX^(42B) ₃,—OCH₂X^(42B), —OCHX^(42B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(43B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(43B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(43B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(43B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(43B)-substituted or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^(43B)-substituted orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(42B) isindependently oxo,halogen, —CX^(42B) ₃, —CHX^(42B) ₂, —CH₂X^(42B), —OCX^(42B) ₃,—OCH₂X^(42B), —OCHX^(42B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(42B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(42B) is independently unsubstituted methyl. Inembodiments, R^(42B) is independently unsubstituted ethyl.

R^(43B) is independently oxo,

halogen, —CX^(43B) ₃, —CHX^(43B) ₂, —CH₂X^(43B), —OCX^(43B) ₃,—OCH₂X^(43B), —OCHX^(43B) ₂, —CN, —OH, —NH₂, —C OOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered). X^(43B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(43B) is independently unsubstituted methyl. Inembodiments, R^(43B) is independently unsubstituted ethyl.

In embodiments, R⁸ is hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, orunsubstituted C₁-C₂ alkyl. In embodiments, R⁸ is hydrogen.

In embodiments, X is-F. In embodiments, X is-Cl. In embodiments, Xis-Br. In embodiments, X is —I. In embodiments, X¹ is —F. Inembodiments, X¹ is —Cl. In embodiments, X¹ is —Br. In embodiments, X¹ is—I. In embodiments, X² is —F. In embodiments, X² is —Cl. In embodiments,X² is —Br. In embodiments, X² is —I. In embodiments, X³ is —F. Inembodiments, X³ is —Cl. In embodiments, X³ is —Br. In embodiments, X³ is—I. In embodiments, X⁴ is —F. In embodiments, X⁴ is —Cl. In embodiments,X⁴ is —Br. In embodiments, X⁴ is —I. In embodiments, X⁵ is —F. Inembodiments, X⁵ is —Cl. In embodiments, X⁵ is —Br. In embodiments, X⁵ is—I. In embodiments, X⁶ is —F. In embodiments, X⁶ is —Cl. In embodiments,X⁶ is —Br. In embodiments, X⁶ is —I. In embodiments, X⁷ is —F. Inembodiments, X⁷ is —Cl. In embodiments, X⁷ is —Br. In embodiments, X⁷ is—I. In embodiments, X⁸ is —F. In embodiments, X⁸ is —Cl. In embodiments,X⁸ is —Br. In embodiments, X⁸ is —I.

In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments,n2 is 3. In embodiments, n2 is 4.

In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, m2is 1. In embodiments, m2 is 2.

In embodiments, v1 is 1. In embodiments, v1 is 2. In embodiments, v2is 1. In embodiments, v2 is 2.

In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1is 5. In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments,z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. Inembodiments, z2 is 5.

In some embodiments, a compound as described herein may include multipleinstances of R¹ and/or other variables. In such embodiments, eachvariable may optional be different and be appropriately labeled todistinguish each group for greater clarity. For example, where each R¹is different, they may be referred to, for example, as R^(1.1), R^(1.2),R^(1.3), R^(1.4), R^(1.5), respectively, wherein the definition of R¹ isassumed by R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5). The variablesused within a definition of R¹ and/or other variables that appear atmultiple instances and are different may similarly be appropriatelylabeled to distinguish each group for greater clarity. In someembodiments, the compound is a compound described herein (e.g., in anaspect, embodiment, example, claim, table, scheme, drawing, or figure).

In embodiments, R⁷ is independently alkyl or hydrogen. In embodiments,R⁷ is alkyl. In embodiments, R⁷ is hydrogen. In embodiments, R¹⁰³ isindependently hydrogen or -L²-(Ring B)-(R²) z2. In embodiments, R¹⁰³ ishydrogen. In embodiments, R¹⁰³ is -L²-(Ring B)-(R²)_(z2). Inembodiments, L² is independently —N(R⁶)—, —S—, or —O—. In embodiments,L² is-N(R⁶)—. In embodiments, L² is —S—. In embodiments, L² is —O—. Inembodiments, Ring B is independently an aryl or heteroaryl. Inembodiments, Ring B is an aryl. In embodiments, z2 is an integer from 0to 3. In embodiments, z2 is 0 or 1. In embodiments, z2 is 0. Inembodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, or substituted or unsubstituted alkyl. Inembodiments, R² is independently —CX² ₃, —CHX² ₂, —CH₂X², orunsubstituted alkyl. In embodiments, R² is independently unsubstitutedalkyl. In embodiments, R² is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R² is methyl. In embodiments, R³ is hydrogen orunsubstituted C₁-C₄ alkyl. In embodiments, R³ is propyl. In embodiments,R³ is ethyl. In embodiments, R³ is methyl. In embodiments, R¹⁰¹ isindependently —NH₂, —NO₂, or —N(R⁴)-L¹-R¹⁰². In embodiments, R¹⁰¹ is—NH₂. In embodiments, R¹⁰¹ is, —NO₂. In embodiments, R¹⁰¹ is—N(R⁴)-L¹-R¹⁰², In embodiments, R⁴ is independently hydrogen orunsubstituted alkyl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴is unsubstituted C₁-C₄ alkyl. In embodiments, R⁴ is methyl. Inembodiments, L¹ is independently —C(O)—, —C(O)N(R⁵)—, —C(O)CH₂—,—C(O)CH₂N(R⁵)—, —C(O)N(R⁵)CH₂—, —C(S)—, —C(S)N(R⁵)—, —C(S)CH₂—,—C(S)CH₂N(R⁵)—, or —C(S)N(R⁵)CH₂—, S(O)₂—. In embodiments, L¹ isindependently —C(O)— or —C(O)CH₂₋. In embodiments, L¹ is independently—C(O)—. In embodiments, L¹ is —C(O)N(R⁵)— or —C(O)N(R⁵)CH₂₋. Inembodiments, L¹ is —S(O)₂—. In embodiments, R⁵ is hydrogen orunsubstituted C₁-C₄ alkyl. In embodiments, R⁵ is hydrogen. Inembodiments, R⁵ is propyl. In embodiments, R⁵ is ethyl. In embodiments,R⁵ is methyl. In embodiments, R¹⁰² is substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted unsubstitutedheteroaryl. In embodiments, R¹⁰² is substituted or unsubstituted alkyl.In embodiments, R¹⁰² is substituted or unsubstituted heteroalkyl. Inembodiments, R¹⁰² is substituted heteroalkyl. In embodiments, R¹⁰² issubstituted or unsubstituted cycloalkyl. In embodiments, R¹⁰² issubstituted or unsubstituted heterocycloalkyl. In embodiments, R¹⁰² issubstituted heterocycloalkyl. In embodiments, R¹⁰² is substituted orunsubstituted phenyl. In embodiments, R¹⁰² is unsubstituted phenyl. Inembodiments, R¹⁰² is or substituted unsubstituted heteroaryl. Inembodiments, the compound is 06A, 07A, 08A, 09A, 10A, 11A, 12A, 13A,14A, 15A, 16A, 17A, 18A, 19A, 15B, 16B, 17B, 18B, 19B, 20B, 55C, 56D,57C, 7, 24E, 25E, 26E, or 27E.

In some embodiments, a compound as described herein may include multipleinstances of R² and/or other variables. In such embodiments, eachvariable may optional be different and be appropriately labeled todistinguish each group for greater clarity. For example, where each R²is different, they may be referred to, for example, as R^(2.1), R^(2.2),R^(2.3), R^(2.4), R^(2.5), respectively, wherein the definition of R² isassumed by R^(2.1), R^(2.2), R^(2.3), R^(2.4), R^(2.5). The variablesused within a definition of R² and/or other variables that appear atmultiple instances and are different may similarly be appropriatelylabeled to distinguish each group for greater clarity. In someembodiments, the compound is a compound described herein (e.g., in anaspect, embodiment, example, claim, table, scheme, drawing, or figure).

In embodiments, unless otherwise indicated, a compound described hereinis a racemic mixture of all stereoisomers. In embodiments, unlessotherwise indicated, a compound described herein is a racemic mixture ofall enantiomers. In embodiments, unless otherwise indicated, a compounddescribed herein is a racemic mixture of two opposite stereoisomers. Inembodiments, unless otherwise indicated, a compound described herein isa racemic mixture of two opposite enantiomers. In embodiments, unlessotherwise indicated, a compound described herein is a singlestereoisomer. In embodiments, unless otherwise indicated, a compounddescribed herein is a single enantiomer. In embodiments, the compound isa compound described herein (e.g., in an aspect, embodiment, example,figure, table, scheme, or claim).

In embodiments, the compound is a compound described herein, includingin an example, figure, table, scheme, aspect, embodiment, or claim. Inembodiments, the compound is not a compound described in Argyros et al.,European Journal of Medicinal Chemistry 126 (2017) 954-968. Inembodiments, the compound is not a compound described in U.S.Publication No. US2007/0123494, published May 31, 2007, Seipelt et al.In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In embodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, is included in atherapeutically effective amount.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent) in atherapeutically effective amount. In embodiments of the pharmaceuticalcompositions, the second agent is an agent for treating cancer. Inembodiments, the second agent is an anti-cancer agent. In embodiments,the second agent is a chemotherapeutic. In embodiments, the second agentis an anti-inflammatory agent.

IV. Methods of Treatment

In an aspect is provided a method of treating cancer, the methodincluding administering to a subject in need thereof an effective amountof a compound described herein. In embodiments, the compound is includedin a therapeutically effective amount.

In embodiments, the method includes administering to a subject in needthereof an effective amount of a compound of Formula (XIA). Inembodiments, the method includes administering to a subject in needthereof an effective amount of a compound of Formula (XIA), wherein thecancer is not breast cancer.

In embodiments, the compound has the formula:

wherein R⁷, R⁸, R¹⁰¹, R¹⁰³, and R³ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

R², z2, Ring B, L², R³, R⁷, R⁸, and R¹⁰¹ are as described herein.

In embodiments, the compound has the formula:

R², Z2, Ring B, L², R³, R⁷, R⁸, R⁴, L¹, and R¹⁰² are as describedherein.

In embodiments, the compound has the formula:

R², z2, Ring B, R⁶, R³, R⁷, R⁸, R⁴, and L are as described herein.

In embodiments, R⁷ is independently a substituted or unsubstituted alkylor hydrogen. In embodiments, R⁷ is a substituted or unsubstituted alkyl.In embodiments, R⁷ is a substituted alkyl. In embodiments, R⁷ is anunsubstituted alkyl. In embodiments, R⁷ is hydrogen. In embodiments,R¹⁰³ is independently hydrogen or -L²-(Ring B)-(R²)_(z2). Inembodiments, R¹⁰³ is hydrogen. In embodiments, R¹⁰³ is -L²-(RingB)-(R²)_(z2). In embodiments, L² is independently —N(R⁶)—, —S—, or —O—.In embodiments, L² is-N(R⁶)—. In embodiments, L² is —S—. In embodiments,L² is —O—. In embodiments, Ring B is independently a substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Inembodiments, Ring B is a substituted or unsubstituted aryl. Inembodiments, Ring B is a substituted aryl. In embodiments, Ring B is anunsubstituted aryl. In embodiments, z2 is an integer from 0 to 3. Inembodiments, z2 is 0 or 1. In embodiments, z2 is 0. In embodiments, R²is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, or substituted or unsubstituted alkyl. In embodiments, R² isindependently —CX² ₃, —CHX² ₂, —CH₂X², or unsubstituted alkyl. Inembodiments, R² is independently unsubstituted alkyl. In embodiments, R²is independently unsubstituted C₁-C₄ alkyl. In embodiments, R² isunsubstituted methyl. In embodiments, R³ is hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R³ is unsubstituted propyl. In embodiments,R³ is unsubstituted ethyl. In embodiments, R³ is unsubstituted methyl.In embodiments, R¹⁰¹ is independently —NH₂, —NO₂, or —N(R⁴)-L¹-R¹⁰², Inembodiments, R¹⁰¹ is —NH₂. In embodiments, R¹⁰¹ is —NO₂. In embodiments,R¹⁰¹ is —N(R⁴)-L¹-R¹⁰². In embodiments, R⁴ is independently

hydrogen or unsubstituted alkyl. In embodiments, R⁴ is hydrogen. Inembodiments, R⁴ is unsubstituted C₁-C₄ alkyl. In embodiments, R⁴ isunsubstituted methyl. In embodiments, L¹ is independently —C(O)—,—C(O)N(R⁵)—, —C(O)CH₂—, —C(O)CH₂N(R⁵)—, —C(O)N(R⁵)CH₂—, —C(S)—,—C(S)N(R⁵)—, —C(S)CH₂—, —C(S)CH₂N(R⁵)—, —C(S)N(R⁵)CH₂—, or —S(O)₂—. Inembodiments, L¹ is independently —C(O)— or —C(O)CH₂₋. In embodiments, L¹is independently —C(O)—. In embodiments, L¹ is —C(O)N(R⁵)— or—C(O)N(R⁵)CH₂₋. In embodiments, L¹ is —S(O)₂—. In embodiments, R⁵ ishydrogen or unsubstituted C₁-C₄ alkyl. In embodiments, R⁵ is hydrogen.In embodiments, R⁵ is unsubstituted propyl. In embodiments, R⁵ isunsubstituted ethyl. In embodiments, R⁵ is unsubstituted methyl. Inembodiments, R¹⁰² is substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted unsubstituted heteroaryl. Inembodiments, R¹⁰² is substituted or unsubstituted alkyl. In embodiments,R¹⁰² is substituted or unsubstituted heteroalkyl. In embodiments, R¹⁰²is substituted heteroalkyl. In embodiments, R¹⁰² is substituted orunsubstituted cycloalkyl. In embodiments, R¹⁰² is substituted orunsubstituted heterocycloalkyl. In embodiments, R¹⁰² is substitutedheterocycloalkyl. In embodiments, R¹⁰² is substituted or unsubstitutedphenyl. In embodiments, R¹⁰² is unsubstituted phenyl. In embodiments,R¹⁰² is substituted or unsubstituted heteroaryl. In embodiments, thecompound is 06A, 07A, 08A, 09A, 10A, 11 A, 12A, 13A, 14A, 15A, 16A, 17A,18A, 19A, 15B, 16B, 17B, 18B, 19B, 20B, 55C, 56D, 57C, 7, 24E, 25E, 26E,or 27E.

In embodiments, the cancer is lung cancer. In embodiments, the cancer issmall cell lung cancer. In embodiments, the cancer is non-small celllung cancer. In embodiments, the cancer is prostate cancer. Inembodiments, the cancer is hormone sensitive prostate cancer. Inembodiments, the cancer is hormone refractory prostate cancer. Inembodiments, the cancer is melanoma. In embodiments, the cancer islymphoma. In embodiments, the cancer is sarcoma. In embodiments, thecancer is breast cancer. In embodiments, the cancer is ovarian cancer.In embodiments, the cancer is pancreatic cancer. In embodiments, thecancer is bladder cancer. In embodiments, the cancer is bone cancer. Inembodiments, the cancer is brain cancer. In embodiments, the cancer iscervical cancer. In embodiments, the cancer is colorectal cancer. Inembodiments, the cancer is esophageal cancer. In embodiments, the canceris gastric cancer. In embodiments, the cancer is liver cancer. Inembodiments, the cancer is head and neck cancer. In embodiments, thecancer is kidney cancer. In embodiments, the cancer is myeloma. Inembodiments, the cancer is leukemia. In embodiments, the cancer isthyroid cancer. In embodiments, the cancer is metastatic cancer. Inembodiments, the cancer is not breast cancer.

In embodiments, the method includes administering a second agent (e.g.therapeutic agent). In embodiments, the method includes administering asecond agent (e.g. therapeutic agent) in a therapeutically effectiveamount. In embodiments, the second agent is an agent for treatingcancer. In embodiments, the second agent is an anti-cancer agent. Inembodiments, the second agent is a chemotherapeutic.

In an aspect is provided a method of treating a proliferative disease,the method including administering to a subject in need thereof aneffective amount of a compound described herein. In embodiments, thecompound is included in a therapeutically effective amount. Inembodiments, the proliferative disease is a disease described in Sponand Harris (Am J Med. 1981 June; 70(6): 1231-5) which is incorporatedherein by reference in its entirety.

V. Methods of Inhibition

In an aspect is provided a method of inhibiting cell proliferation, themethod including contacting a cell with a compound described herein. Inembodiments, the method includes contacting the cell with an effectiveamount of the compound. In embodiments, the method includes contactingthe cell with a second agent (e.g. therapeutic agent). In embodiments,the method includes contacting the cell with a second agent (e.g.therapeutic agent) in an effective amount. In embodiments, the secondagent is an agent for treating cancer. In embodiments, the second agentis an anti-cancer agent. In embodiments, the second agent is achemotherapeutic. In embodiments, the cell forms part of an organism. Inembodiments, the organism is a mammal. In embodiments, the cell is acancer cell. In embodiments, the cell is a lung cancer cell. Inembodiments, the cell is a small cell lung cancer cell. In embodiments,the cell is a non-small cell lung cancer cell. In embodiments, the cellis a prostate cancer cell. In embodiments, the cell is a melanoma cell.

In embodiments, the cell is A549 non-small cell lung cancer cell. Inembodiments, the cell is DMS273 small cell lung cancer cell. Inembodiments, the cell is H69 small cell lung cancer cell. Inembodiments, the cell is H513 non-small cell lung cancer cell. Inembodiments, the cell is H2461 non-small cell lung cancer cell. Inembodiments, the cell is DMS114 small cell lung cancer cell. Inembodiments, the cell is H358 non-small cell lung cancer cell. Inembodiments, the cell is H2596 non-small cell lung cancer cell. Inembodiments, the cell is DU145 prostate cancer cell. In embodiments, thecell is A2058 melanoma cell.

In embodiments, the cell is an A2058 melanoma cell. In embodiments, thecell is a melanoma cell. In embodiments, the cell is a DU145 prostatecancer cell. In embodiments, the cell is a prostate cancer cell. Inembodiments, the cell is an A549 cell, DMS273 cell, H69 cell, H513 cell,H2461 cell, DMS114 cell, H358 cell, or H2596 cell. In embodiments, thecell is an A549 cell. In embodiments, the cell is a DMS273 cell. Inembodiments, the cell is a H69 cell. In embodiments, the cell is a H513cell. In embodiments, the cell is a H2461 cell. In embodiments, the cellis a DMS114 cell. In embodiments, the cell is a H358 cell. Inembodiments, the cell is a H2596 cell.

In embodiments, the method includes administering to a subject in needthereof an effective amount of a compound of Formula (XIA). Inembodiments, the method includes administering to a subject in needthereof an effective amount of a compound of Formula (XIA), wherein thecancer is not breast cancer.

In embodiments, the compound has the formula:

wherein R7, R8, R101, R103, and R3 are as described herein, includingembodiments.

In embodiments, the compound has the formula:

R², z2, Ring B, L², R³, R⁷, R⁸, and R¹⁰¹ are as described herein.

In embodiments, the compound has the formula:

R², Z2, Ring B, L², R³, R⁷, R⁸, R⁴, L¹, and R¹⁰² are as describedherein.

In embodiments, the compound has the formula:

R², z2, Ring B, R⁶, R³, R⁷, R⁸, R⁴, and L are as described herein.

In embodiments, R⁷ is independently a substituted or unsubstituted alkylor hydrogen. In embodiments, R⁷ is a substituted or unsubstituted alkyl.In embodiments, R⁷ is a substituted alkyl. In embodiments, R⁷ is anunsubstituted alkyl. In embodiments, R⁷ is hydrogen. In embodiments,R¹⁰³ is independently hydrogen or -L²-(Ring B)-(R²)_(z2). Inembodiments, R¹⁰³ is hydrogen. In embodiments, R¹⁰³ is -L²-(RingB)-(R²)_(z2). In embodiments, L² is independently —N(R⁶)—, —S—, or —O—.In embodiments, L² is-N(R⁶)—. In embodiments, L² is —S—. In embodiments,L² is —O—. In embodiments, Ring B is independently a substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Inembodiments, Ring B is a substituted or unsubstituted aryl. Inembodiments, Ring B is a substituted aryl. In embodiments, Ring B is anunsubstituted aryl. In embodiments, z2 is an integer from 0 to 3. Inembodiments, z2 is 0 or 1. In embodiments, z2 is 0. In embodiments, R²is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, or substituted or unsubstituted alkyl. In embodiments, R² isindependently —CX² ₃, —CHX² ₂, —CH₂X², or unsubstituted alkyl. Inembodiments, R² is independently unsubstituted alkyl. In embodiments, R²is independently unsubstituted C₁-C₄ alkyl. In embodiments, R² isunsubstituted methyl. In embodiments, R³ is hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R³ is propyl. In embodiments, R³ is ethyl.In embodiments, R³ is methyl. In embodiments, R¹⁰¹ is independently—NH₂, —NO₂, or —N(R⁴)-L¹-R¹⁰². In embodiments, R¹⁰¹ is —NH₂. Inembodiments, R¹⁰¹ is, —NO₂. In embodiments, R¹⁰¹ is —N(R⁴)-L¹-R¹⁰². Inembodiments, R⁴ is independently hydrogen or unsubstituted alkyl. Inembodiments, R⁴ is hydrogen. In embodiments, R⁴ is unsubstituted C₁-C₄alkyl. In embodiments, R⁴ is unsubstituted methyl. In embodiments, L¹ isindependently —C(O)—, —C(O)N(R⁵)—, —C(O)CH₂—, —C(O)CH₂N(R⁵)—,—C(O)N(R⁵)CH₂—, —C(S)—, —C(S)N(R⁵)—, —C(S)CH₂—, —C(S)CH₂N(R⁵)—,—C(S)N(R⁵)CH₂—, or —S(O)₂—. In embodiments, L¹ is independently —C(O)—or —C(O)CH₂—. In embodiments, L¹ is independently —C(O)—. Inembodiments, L¹ is —C(O)N(R⁵)— or —C(O)N(R⁵)CH₂—. In embodiments, L¹ is—S(O)₂—. In embodiments, R⁵ is hydrogen or unsubstituted C₁-C₄ alkyl. Inembodiments, R⁵ is hydrogen. In embodiments, R⁵ is unsubstituted propyl.In embodiments, R⁵ is unsubstituted ethyl. In embodiments, R⁵ isunsubstituted methyl. In embodiments, R¹⁰² is substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substitutedunsubstituted heteroaryl. In embodiments, R¹⁰² is substituted orunsubstituted alkyl. In embodiments, R¹⁰² is substituted orunsubstituted heteroalkyl. In embodiments, R¹⁰² is substitutedheteroalkyl. In embodiments, R¹⁰² is substituted or unsubstitutedcycloalkyl. In embodiments, R¹⁰² is substituted or unsubstitutedheterocycloalkyl. In embodiments, R¹⁰² is substituted heterocycloalkyl.In embodiments, R¹⁰² is substituted or unsubstituted phenyl. Inembodiments, R¹⁰² is unsubstituted phenyl. In embodiments, R¹⁰² issubstituted or unsubstituted heteroaryl. In embodiments, the compound is06A, 07A, 08A, 09A, 10A, 11 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A,15B, 16B, 17B, 18B, 19B, 20B, 55C, 56D, 57C, 7, 24E, 25E, 26E, or 27E.

VI. Embodiments

Embodiment 1. A compound having the formula:

wherein, Ring A is an aryl or heteroaryl; R¹ is independently halogen,—CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B), —N(O)_(m1),—NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C), —C(O)NR^(1A)R^(1B),—OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),—NR^(1A)OR^(1C), —N₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is aninteger from 0 to 5; Ring B is an aryl or heteroaryl; R² isindependently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX²₂, —CN, —SO_(ll2)R^(2D), —SO_(v2)NR^(2A)R^(2B), —NHC(O)NR^(2A)R^(2B),—N(O)_(m2), —NR^(2A)R^(2B), —C(O)R^(2C), —C(O)—OR^(2C),—C(O)NR^(2A)R^(2B), —OR^(2D), —NR^(2A)SO₂R^(2D), —NR^(2A)C(O)R^(2C),—NR^(2A)C(O)OR^(2C), —NR^(2A)OR^(2C), —N₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; z2 is an integer from 0 to 5; R³ is independently hydrogen,—CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), —OR^(3A), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,—C(O)R^(4A), —C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Lisabond or —N(R⁵)—; R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,—C(O)R^(5A), —C(O)OR^(5A), —C(O)NR^(5A)R^(5B), substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R⁶ isindependently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —C(O)R^(6A),—C(O)OR^(6A), —C(O)NR^(6A)R^(6B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl; R⁷ is independently hydrogen,—CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —C(O)R^(7A),—C(O)OR^(7A), —C(O)NR^(7A)R^(7B), —OR^(7A), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁸ is independently hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸ ₂, —CN, —C(O)R^(8A), —C(O)OR^(8A),—C(O)NR^(8A)R^(8B), —OR^(8A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; EachR^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(4A), R^(4B), R^(5A), R^(5B), R^(6A), R^(6B), R^(7A), R^(7B),R^(8A), and R^(8B) is independentlyhydrogen, —CX₃, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A) and R^(1B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(2A) and R^(2B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(3A) andR^(3B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(4A) and R^(4B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(5A) and R^(5B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(6A) and R^(6B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(7A) andR^(7B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(8A) and R^(8B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; each X, X¹, X², X³, X⁴, X⁵, X⁶, X⁷, and X⁸ isindependently —F, —Cl, —Br, or —I; n1 and n2 are independently aninteger from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2.

Embodiment 2. The compound of embodiment 1, wherein L is —N(R⁵)—.

Embodiment 3. The compound of embodiment 1, wherein L is a bond.

Embodiment 4. The compound of one of embodiments 1 to 3, wherein R⁸ ishydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, or unsubstituted C₁-C₂ alkyl.

Embodiment 5. The compound of one of embodiments 1 to 3, wherein R⁸ ishydrogen.

Embodiment 6. The compound of one of embodiments 1 to 5, wherein R⁷ ishydrogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, or unsubstituted C₁-C₂ alkyl.

Embodiment 7. The compound of one of embodiments 1 to 5, wherein R⁷ ishydrogen.

Embodiment 8. The compound of embodiment 1 having the formula:

Embodiment 9. The compound of one of embodiments 1 to 8, wherein R⁶ ishydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, or unsubstituted C₁-C₂ alkyl.

Embodiment 10. The compound of one of embodiments 1 to 8, wherein R⁶ ishydrogen.

Embodiment 11. The compound of one of embodiments 1 to 10, wherein R⁵ ishydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, or unsubstituted C₁-C₂ alkyl.

Embodiment 12. The compound of one of embodiments 1 to 10, wherein R⁵ ishydrogen.

Embodiment 13. The compound of one of embodiments 1 to 12, wherein R⁴ ishydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, or unsubstituted C₁-C₂ alkyl.

Embodiment 14. The compound of one of embodiments 1 to 12, wherein R⁴ ishydrogen.

Embodiment 15. The compound of one of embodiments 1 to 14, wherein R³ is—CX³ ₃, —CHX³ ₂, —CH₂X³, or unsubstituted C₁-C₃ alkyl.

Embodiment 16. The compound of one of embodiments 1 to 14, wherein R³ isunsubstituted methyl.

Embodiment 17. The compound of embodiment 1 having the formula:

Embodiment 18. The compound of one of embodiments 1 to 17, wherein RingA is phenyl or 5 to 6 membered heteroaryl.

Embodiment 19. The compound of one of embodiments 1 to 17, wherein RingA is phenyl.

Embodiment 20. The compound of one of embodiments 1 to 19, wherein R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —SCX¹ ₃, —SCHX¹ ₂,—SCH₂X¹, unsubstituted C₁-C₂ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl.

Embodiment 21. The compound of one of embodiments 1 to 19, wherein R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, or unsubstituted C₁-C₂alkyl.

Embodiment 22. The compound of one of embodiments 1 to 19, wherein R¹ isindependently halogen, —CF₃, —CHF₂, —CH₂F, —CH₃, —SCF₃, —SCHF₂, —SCH₂F,or —SCH₃

Embodiment 23. The compound of one of embodiments 1 to 19, wherein R¹ isindependently halogen, —CX³ ₃, or —SCH₃.

Embodiment 24. The compound of one of embodiments 1 to 19, wherein R¹ isindependently —F, —Cl, —SCH₃, or —CF₃.

Embodiment 25. The compound of one of embodiments 1 to 24, wherein z1 is2.

Embodiment 26. The compound of one of embodiments 1 to 24, wherein z1 is1.

Embodiment 27. The compound of one of embodiments 1 to 24, wherein z1 is0.

Embodiment 28. The compound of embodiment 1 having the formula:

Embodiment 29. The compound of embodiment 1 having the formula:

Embodiment 30. The compound of embodiment 1 having the formula:

Embodiment 31. The compound of embodiment 1 having the formula:

Embodiment 32. The compound of one of embodiments 1 to 31, wherein RingB is a phenyl or 5 to 6 membered heteroaryl.

Embodiment 33. The compound of one of embodiments 1 to 31, wherein RingB is a phenyl.

Embodiment 34. The compound of one of embodiments 1 to 33, wherein R² isindependently —OCX² ₃, —OCH₂X², —OCHX² ₂, —C(O)R^(2C), —C(O)OR^(2C),—OR^(2D), or —NR^(2A)C(O)R^(2C); and; Each R^(2A), R^(2B), R^(2C), andR^(2D) is independently hydrogen, —CX₃, —CHX₂, —CH₂X, unsubstitutedC₁-C₂ alkyl.

Embodiment 35. The compound of one of embodiments 1 to 33, wherein R² isindependently —OCF₃, —OCH₂F, —OCHF₂, —C(O)OH, —C(O)OCH₂CH₃, —OCH₃, or—NHC(O)CH₃.

Embodiment 36. The compound of one of embodiments 1 to 35, wherein z2 is3.

Embodiment 37. The compound of one of embodiments 1 to 35, wherein z2 is2.

Embodiment 38. The compound of one of embodiments 1 to 35, wherein z2 is1.

Embodiment 39. The compound of one of embodiments 1 to 35, wherein z2 is0.

Embodiment 40. The compound of embodiment 38 having the formula:

Embodiment 41. The compound of embodiment 38 having the formula:

Embodiment 42. The compound of embodiment 39 having the formula:

Embodiment 43. The compound of embodiment 38 having the formula:

Embodiment 44. The compound of embodiment 38 having the formula:

Embodiment 45. The compound of embodiment 39 having the formula:

Embodiment 46. The compound of embodiment 38 having the formula:

Embodiment 47. The compound of embodiment 38 having the formula:

Embodiment 48. The compound of embodiment 39 having the formula:

Embodiment 49. The compound of embodiment 38 having the formula:

Embodiment 50. The compound of embodiment 38 having the formula:

Embodiment 51. The compound of embodiment 39 having the formula:

Embodiment 52. A pharmaceutical composition comprising a compound of oneof embodiments 1 to 51 or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Embodiment 53. The pharmaceutical composition of embodiment 52,comprising a therapeutically effective amount of said compound.

Embodiment 54. A method of treating cancer, said method comprisingadministering to a subject in need thereof an effective amount of acompound of one of embodiments 1 to 5E

Embodiment 55. The method of embodiment 54, wherein the cancer is lungcancer.

Embodiment 56. The method of embodiment 54, wherein the cancer is smallcell lung cancer.

Embodiment 57. The method of embodiment 54, wherein the cancer isnon-small cell lung cancer.

Embodiment 58. The method of embodiment 54, wherein the cancer isprostate cancer.

Embodiment 59. The method of embodiment 54, wherein the cancer ishormone sensitive prostate cancer.

Embodiment 60. The method of embodiment 54, wherein the cancer ishormone refractory prostate cancer.

Embodiment 61. The method of embodiment 54, wherein the cancer ismelanoma.

Embodiment 62. The method of embodiment 54, wherein the cancer is lungcancer, prostate cancer, melanoma, lymphoma, sarcoma, breast cancer,ovarian cancer, pancreatic cancer, bladder cancer, bone cancer, braincancer, cervical cancer, colorectal cancer, esophageal cancer, gastriccancer, liver cancer, head and neck cancer, kidney cancer, myeloma,leukemia, or thyroid cancer.

EXAMPLES Example 1. Compounds

TABLE 1 Viability Viability % CTL % CTL A2058 DU145 Name Structuremelanoma prostate 06A

85 94 07A

82 122 08A

80 96 09A

74 103 10A

93 95 11A

87 106 12A

84 99 13A

94 86 14A

106 101 15A

73 104 16A

96 99 17A

79 98 18A

74 89 19A

59 122 15B

61 113 16B

84 120 17B

56 101 18B

83 124 19B

89 113 20B

84 89 16

4 10 17

2 0 12

69 93 55C

91 95 56D

81 108 57C

94 126

TABLE 2 Viability Viability (% CTL) (% CTL) at 10 μM at 10 μM A2058DU145 Code Structure melanoma prostate  7

98 76 24E

84 102 25E

85 83 26E

93 85 27E

85 82  8

81 90  9

66 82 10

86 97 13

84 77 11

83 105 14

75 80 15

5 4

TABLE 3 Name Structure 16

4 10 17

2 0

TABLE 4 Viability Viability % CTL % CTL A2058 DU145 melanoma prostatecode Structure (10 μM) (10 μM ) 18

7 6 19

60 50 28

35 40 35

98 82 30

118 64 32

65 76 29

37 48 36

113 77 31

119 62 33

109 55 34

116 81

TABLE 5 16 17 18 29 28 (IC50 (IC50 (IC50 (IC50 (IC50 Cmpd/cell μM) μM)μM) μM) μM) A549 1.54 0.92 NSCLC DMS273 1.09 0.32 small cell lung cancerH69 small 0.98 0.51 cell lung cancer H513 1.26 0.69 NSCLC H2461 1.71 0.8NSCLC DMS114 3.15 0.72 small cell lung cancer H358 1.97 1.18 NSCLC H25961.07 0.62 NSCLC DU145 1.72 1.04 2.4 12.8 9.9 prostate cancer A2058 1.291.13 1.3 6.1 7.1 melanoma

Example 2. Synthesis

General Information:

Melting points were determined on a Bûchi apparatus and are uncorrected.¹H NMR spectra were recorded on a Bruker Avance III 600 instrument,whereas ¹³C NMR spectra were recorded on a Bruker Avance III 600 or aBruker AC 200 spectrometer in deuterated solvents and were referenced toTMS (S scale). Flash chromatography was performed on Merck silica gel 60(0.040-0.063 mm). Analytical thin layer chromatography (TLC) was carriedout on precoated (0.25 mm) Merck silica gel F-254 plates. The purity ofall the synthesized compounds was >95% as ascertained by elementalanalysis. Elemental analyses were undertaken using a PerkinElmer PE 240Celemental analyzer (Norwalk, Conn., U.S.) and the measured values for C,H, and N were within ±0.4% of the theoretical values.

Synthesis Example 1 Synthesis of Substituted Benzamides 8-12

The synthesis of the target amides 8-12 was performed using3-chloro-6-methyl-7-nitropyrido[2,3-b]pyrazine (5) as the keyintermediate. The latter was prepared through a four-step procedure,starting from 6-methylpyridin-2-amine (1), as previously described inthe literature. Briefly, pyridine 1 was nitrated with excess of nitricacid to result into the 3,5-dinitro derivative 2 (Step 1, H. Ritter, H.Licht, J. Heterocyclic Chem. 32 (1995) 585-590). Compound 2 wassubjected to selective reduction of the 3-nitro group to provide diamine3 (Step 2, N. Lougiakis, P. Marakos, et al, Chem. Pharm. Bull. 63 (2015)134-142). The diamine 3 was converted upon treatment with ethylglyoxalate to the pyridopyrazinone 4 (Step 3), from which, upontreatment with phosphorus oxychloride in the presence of triethylamine,the chloride 5 was prepared (Step 4, O. Argyros, N. Lougiakis, et al,Eur. J. Med. Chem. 126 (2017) 954-968).

Step 5: 6-Methyl-7-nitro-N-phenylpyrido[2,3-b]pyrazin-3-amine (6)

A mixture of chloro compound 5 (540 mg, 2.41 mmol) and aniline (0.48 mL,5.3 mmol), in 20 mL of absolute ethanol was refluxed, under argon, for 1hour. Upon cooling, 80 mL of cold water was added in the flask and theyellow precipitate was filtered, washed with water and air-dried toprovide 675 mg of pure amine 6 as a yellow solid. Yield 100%. M.p.>300°C._((dec.))(EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.85 (s, 3H), 7.15 (t,1H, J=7.3 Hz), 7.43 (t, 2H, J=8.0 Hz), 7.98 (d, 2H, J=7.8 Hz), 8.62 (s,1H), 8.77 (s, 1H), 10.63 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz, DMSO-d₆)δ 24.52, 119.99, 123.87, 128.31, 129.06, 133.62, 138.96, 141.50, 144.18,152.20, 153.20, 155.46. HRMS (ESI) m/z: calcd. for C₁₄H₁₂N₅O₂:[M1+H]⁺=282.0986, found 282.0984.

Step 6: 6-Methyl-N³-phenylpyrido[2,3-b]pyrazine-3,7-diamine (7)

Triethylsilane (3.2 mL, 20 mmol) was added dropwise into a suspension ofnitro derivative 6 (560 mg, 1.99 mmol) and 60 mg of 10% Pd/C in 15 mL ofdry methanol, under argon, and this mixture was stirred at roomtemperature for 4 hours. Then, the solution was filtered through acelite pad to remove the catalyst, the solvent was evaporated and theresidue was dry-packed and purified by column chromatography, using amixture of 99/I of dichloromethane/methanol as the eluent, providing 460mg of compound 7 as a yellow solid. Yield 92%. M.p.>300° C._((dec.))(EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.49 (s, 3H), 5.41 (brs, 2H, D₂Oexch.), 6.98 (t, 1H, J=7.3 Hz), 7.27 (s, 1H), 7.35 (t, 2H, J=8.0 Hz),7.95 (d, 2H, J=7.7 Hz), 8.42 (s, 1H), 9.70 (brs, 1H, D₂O exch.). ¹³C-NMR(50 MHz, DMSO-d₆) δ 21.45, 114.83, 118.09, 121.32, 128.71, 131.95,139.44, 140.79, 141.29, 141.86, 149.02, 150.99. HRMS (ESI) m/z: calcd.for C₁₄H₁₄N₅: [M1+H]⁺=252.1244, found 252.1239.

Step 7: General Procedure for the Synthesis of Amides 8-12

Benzoyl chloride or the appropriate substituted benzoyl chloride (0.35mmol) and triethylamine (0.049 mL, 0.35 mmol) were added into asuspension of 7 (80 mg, 0.32 mmol) in 8 mL of dry tetrahydrofuran andthe reaction mixture was stirred at room temperature for 24 hours. Thesolvent was then removed under reduced pressure, water was added in theflask and the precipitate was extracted with ethyl acetate (3×40 mL).The organic extracts were dried (Na₂SO₄) and concentrated to dryness andthe residue was dry-packed and purified by column chromatography,providing amides 8-12.

N-(6-Methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)benzamide (8)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 3/7 of cyclohexane/ethyl acetate as the eluent. 100mg of amide 8 were obtained as a yellow solid. Yield 88%. M.p. 247-8° C.(EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.65 (s, 3H), 7.08 (t, 1H, J=7.3Hz), 7.42 (t, 2H, J=7.9 Hz), 7.57 (t, 2H, J=7.6 Hz), 7.64 (t, 1H, J=7.3Hz), 8.01-8.06 (m, 4H), 8.26 (s, 1H), 8.59 (s, 1H), 10.17 (brs, 1H, D₂Oexch.), 10.20 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz, DMSO-d₆) δ 21.79,119.00, 122.49, 127.76, 128.49, 128.82, 129.76, 129.95, 131.86, 132.55,134.07, 139.92, 141.12, 147.54, 151.60, 158.28, 165.88. HRMS (ESI) m/z:calcd. for C₂₁H₁₈N₅O: [M1+H]⁺=356.1506, found 356.1502. Anal. Calcd forC₂₁H₁₇N₅O: C, 70.97; H, 4.82; N, 19.71. Found: C, 70.83; H, 4.67; N,20.01.

4-Methyl-N-(6-methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)benzamide(9)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 7/3 of dichloromethane/ethyl acetate as the eluent.110 mg of amide 9 were obtained as a yellow solid. Yield 94%. M.p. 246°C. (EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.41 (s, 3H), 2.64 (s, 3H), 7.08(t, 1H, J=7.3 Hz), 7.38 (d, 2H, J=7.9 Hz), 7.42 (t, 2H, J=7.9 Hz), 7.95(d, 2H, J=8.0 Hz), 8.02 (d, 2H, J=8.2 Hz), 8.25 (s, 1H), 8.59 (s, 1H),10.11 (brs, 1H, D₂O exch.), 10.17 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz,DMSO-d₆) δ 21.03, 21.80, 119.00, 122.50, 127.80, 128.84, 129.02, 129.78,130.06, 131.24, 132.53, 139.94, 141.12, 141.92, 147.49, 151.59, 158.30,165.72. HRMS (ESI) m/z: calcd. for C₂₂H₂₀N₅O: [M1+H]⁺=370.1662, found370.1656. Anal. Calcd for C₂₂H₁₉N₅O: C, 71.53; H, 5.18; N, 18.96. Found:C, 71.41; H, 5.09; N, 19.16.

N-(6-Methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)-4-nitrobenzamide(10)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 1/1 of dichioromethane/ethyl acetate as the eluent.115 mg of amide 10 were obtained as a yellow solid. Yield 90%. M.p.299-301° C. (EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.65 (s, 3H), 7.07 (t,1H, J=7.3 Hz), 7.42 (t, 2H, J=7.8 Hz), 8.03 (d, 2H, J=7.8 Hz), 8.24-8.29(m, 3H), 8.42 (d, 2H, J=8.6 Hz), 8.60 (s, 1H), 10.20 (brs, 1H, D₂Oexch.), 10.54 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz, DMSO-d₆) δ 21.78,119.06, 122.57, 123.65, 128.83, 129.32, 129.39, 129.69, 132.79, 139.78,139.87, 141.29, 147.80, 149.35, 151.71, 158.13, 164.43. HRMS (ESI) m/z:calcd. for C₂₁H₁₇N₆O₃: [M1+H]⁺=401.1357, found 401.1355. Anal. Calcd forC₂₁H₁₆N₆O₃: C, 63.00; H, 4.03; N, 20.99. Found: C, 62.81; H, 4.17; N,21.16.

3,4,5-Trimethoxy-N-(6-methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)benzamide(11)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 6/4 of dichioromethane/ethyl acetate as the eluent.130 mg of amide 11 were obtained as a yellow solid. Yield 92%. M.p.162-4° C. (EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.63 (s, 3H), 3.75 (s,3H), 3.89 (s, 6H), 7.08 (t, 1H, J=7.3 Hz), 7.38 (s, 2H), 7.42 (t, 2H,J=7.9 Hz), 8.03 (d, 2H, J=7.9 Hz), 8.21 (s, 1H), 8.60 (s, 1H), 10.15(brs, 1H, D₂O exch.), 10.18 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz,DMSO-d₆) δ 21.82, 56.11, 60.14, 105.41, 119.03, 122.52, 128.83, 129.07,129.77, 129.96, 132.75, 139.92, 140.59, 141.17, 147.64, 151.65, 152.72,158.54, 165.22. HRMS (ESI) m/z calcd. for C₂₄H₂₄N₅O₄: [M1+H]⁺=446.1823,found 446.1818. Anal. Calcd for C₂₄H₂₃N₅O₄: C, 64.71; H, 5.20; N, 15.72.Found: C, 64.88; H, 5.12; N, 15.49.

N-(6-Methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)-3-(trifluoromethyl)benzamide(12)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 3/7 of cyclohexane/ethyl acetate as the eluent. 130mg of amide 12 were obtained as a yellow solid. Yield 95%. M.p. 177-9°C. (EtOAc/n-hexane). ¹H-NMR (600 MHz, DMSO-d) δ 2.64 (s, 3H), 7.09 (t,1H, J=7.3 Hz), 7.42 (t, 2H, J=8.0 Hz), 7.83 (t, 1H, J=7.9 Hz), 8.03 (m,3H), 8.26 (s, 1H), 8.34 (d, 1H, J=7.9 Hz), 8.38 (s, 1H), 8.60 (s, 1H),10.20 (brs, 1H, D₂O exch.), 10.47 (brs, 1H, D₂O exch.). ¹³C-NMR (151MHz, DMSO-d₆) δ 21.82, 119.07, 122.58, 123.08, 124.42, 124.88, 128.44,128.86, 129.00, 129.21, 129.42, 129.57, 129.64, 129.74, 129.89, 131.92,132.97, 135.03, 139.91, 141.27, 147.80, 151.72, 158.37, 164.57. HRMS(ESI) m/z: calcd. for C₂₂H₁₇F₃N₅O: [M1+H]⁺=424.1380, found 424.1373.Anal. Calcd for C₂₂H₁₆F₃N₅O: C, 62.41; H, 3.81; N, 16.54. Found: C,62.27; H, 3.76; N, 16.67.

Synthesis Example 2 Synthesis ofN-(6-methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)-4-(3-phenylureido)benzamide(14) Step 1:4-Amino-N-(6-methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)benzamide(13)

Triethylsilane (1.5 mL, 9.4 mmol) was added dropwise into a suspensionof nitro compound 10 (200 mg, 0.5 mmol, its synthesis is described atStep 7, Example 1) and 50 mg of 10% Pd/C in 12 mL of dry methanol, underargon, and this mixture was stirred at room temperature for 4 hours.Then, the solution was filtered through a celite pad to remove thecatalyst, the solvent was evaporated and the residue was dry-packed andpurified by column chromatography, using a mixture of 95/5 ofdichloromethane/methanol as the eluent, providing 140 mg of compound 13as a yellow solid. Yield 76%. M.p. 265° C. (MeOH). ¹H-NMR (600 MHz,DMSO-d₆) δ 2.62 (s, 3H), 5.82 (brs, 2H, D₂O exch.), 6.63 (d, 2H, J=8.6Hz), 7.03 (t, 1H, J=7.3 Hz), 7.41 (t, 2H, J=7.9 Hz), 7.77 (d, 2H, J=8.6Hz), 8.02 (d, 2H, J=7.9 Hz), 8.22 (s, 1H), 8.58 (s, 1H), 9.69 (brs, 1H,D₂O exch.), 10.13 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz, DMSO-d₆) δ21.82, 112.61, 118.94, 120.28, 122.40, 128.81, 129.48, 129.85, 130.72,131.91, 139.99, 140.90, 147.10, 151.44, 152.39, 158.26, 165.61. HRMS(ESI) m/z: calcd. for C₂₁H₁₉N₆O: [M1+H]⁺=371.1615, found 371.1611. Anal.Calcd for C₂₁H₁₈N₆O: C, 68.09; H, 4.90; N, 22.69. Found: C, 68.17; H,4.93; N, 22.76.

Step 2:N-(6-Methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)-4-(3-phenylureido)benzamide(14)

Phenylisocyanate (0.026 mL, 0.24 mmol) was added into a suspension of 13(80 mg, 0.22 mmol) in 8 mL of dry tetrahydrofuran and this reactionmixture was heated at 70° C. for 20 hours. The solvent was removed underreduced pressure and the residue was dry-packed and purified by columnchromatography using a mixture of 2/8 of cyclohexane/ethyl acetate asthe eluent, providing 55 mg of 14 as a yellow solid. Yield 52%. M.p.262-4° C. (dec.) (MeOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.64 (s, 3H), 7.00(t, 1H, J=7.4 Hz), 7.07 (t, 1H, J=7.4 Hz), 7.30 (t, 2H, J=7.4 Hz+8.6Hz), 7.42 (t, 2H, J=7.4 Hz+8.6 Hz), 7.48 (d, 2H, J=8.6 Hz), 7.63 (d, 2H,J=9.0 Hz), 8.02 (m, 4H), 8.25 (s, 1H), 8.59 (s, 1H), 8.80 (brs, 1H, D₂Oexch.), 9.05 (brs, 1H, D₂O exch.), 10.05 (brs, 1H, D₂O exch.), 10.17(brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz, DMSO-d₆) δ 21.83, 117.23, 118.41,119.00, 122.15, 122.48, 126.90, 128.82, 128.90, 129.80, 130.22, 132.37,139.37, 139.96, 141.07, 143.18, 147.41, 151.57, 152.29, 158.31, 165.32.HRMS (ESI) m/z: calcd. for C₂₈H₂₄N₇O₂: [M1+H]⁺=490.1986, found 490.1980.Anal. Calcd for C₂₈H₂₃N₇O₂: C, 68.70; H, 4.74; N, 20.03. Found: C,68.88; H, 4.56; N, 20.22.

Synthesis Example 3 Synthesis of phenylurea derivatives 15-19

Step 1: General procedure for the synthesis of urea derivatives 15-19

Phenyl isocyanate or the appropriate substituted phenyl isocyanate (0.45mmol) was added into a suspension of 7 (80 mg, 0.32 mmol, its synthesisis described at Step 6 of Example 1) in 10 mL of dry tetrahydrofuran andthis reaction mixture was refluxed, under argon, for 20 hours. Thesolvent was then removed under reduced pressure, the residue wasdissolved in a mixture of dichloromethane and methanol, dry-packed andpurified by column chromatography, providing compounds 15-19.

1-(6-Methyl-3-(phenylamino)pyrido[2,3-6]pyrazin-7-yl)-3-phenylurea (15)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 4/6 of cyclohexane/ethyl acetate as the eluent. 90 mgof compound 15 were obtained as a yellow solid. Yield 76%. M.p. 232-4°C. (EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.67 (s, 3H), 7.00 (t, 1H, J=7.4Hz), 7.05 (t, 1H, J=7.4 Hz), 7.32 (t, 2H, J=7.4 Hz+8.2 Hz), 7.40 (t, 2H,J=7.4 Hz+8.2 Hz), 7.50 (d, 2H, J=7.4 Hz), 8.00 (d, 2H, J=7.8 Hz), 8.30(brs, 1H, D₂O exch.), 8.55 (s, 1H), 8.68 (s, 1H), 9.22 (brs, 1H, D₂Oexch.), 10.04 (brs, 1H, D₂O exch.). ¹³C-NMR (50 MHz, DMSO-d₆) δ 21.90,118.22, 118.72, 122.08, 122.13, 124.96, 128.78, 128.88, 130.22, 131.53,139.46, 140.18, 140.79, 145.07, 150.86, 152.61, 153.37. HRMS (ESI) m/z:calcd. for C₂₁H₁₉N₆O: [M1+H]⁺=371.1615, found 371.1609. Anal. Calcd forC₂₁H₁₈N₆O: C, 68.09; H, 4.90; N, 22.69. Found: C, 68.22; H, 4.81; N,22.58.

1-(6-Methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)-3-(3-(trifluoromethyl)phenyl)urea(16)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 100/5 of dichloromethane/methanol as the eluent. 90mg of compound 16 were obtained as a yellow solid. Yield 65%. M.p.236-7° C. (EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.66 (s, 3H), 7.05 (t, 1H,J=7.3 Hz), 7.34 (d, 1H, J=7.6 Hz), 7.39 (t, 2H, J=8.0 Hz), 7.55 (t, 1H,J=7.9 Hz), 7.61 (d, 1H, J=8.2 Hz), 7.99 (d, 2H, J=7.8 Hz), 8.05 (s, 1H),8.40 (brs, 1H, D₂O exch.), 8.56 (s, 1H), 8.63 (s, 1H), 9.55 (brs, 1H,D₂O exch.), 10.04 (brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ21.88, 114.13, 118.35, 118.79, 121.83, 122.23, 123.30, 125.10, 125.89,128.81, 129.31, 129.52, 129.73, 129.93, 130.07, 130.15, 131.08, 140.15,140.38, 140.92, 145.46, 151.01, 152.69, 153.89. HRMS (ESI) m/z: calcd.for C₂₂H₁₈F₃N₆O: [M1+H]⁺=439.1489, found 439.1484. Anal. Calcd forC₂₂H₁₇F₃N₆O: C, 60.27; H, 3.91; N, 19.17. Found: C, 60.33; H, 3.96; N,19.01.

1-(3-Chloro-4-fluorophenyl)-3-(6-methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)urea(17)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 100/4 of dichloromethane/methanol as the eluent. 110mg of compound 17 were obtained as a yellow solid. Yield 82%. M.p.215-6° C. (EtOH). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.65 (s, 3H), 7.05 (t, 1H,J=7.3 Hz), 7.30-7.33 (m, 1H), 7.36 (t, 1H, J=9.0 Hz), 7.39 (t, 2H, J=8.0Hz), 7.86 (dd, 1H, J=6.8 Hz+2.5 Hz), 7.99 (d, 2H, J=7.8 Hz), 8.34 (brs,1H, D₂O exch.), 8.55 (s, 1H), 8.61 (s, 1H), 9.36 (brs, 1H, D₂O exch.),10.03 (brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ 21.89, 116.93,117.07, 118.52, 118.57, 118.78, 119.22, 119.34, 119.56, 122.21, 125.76,128.81, 130.16, 131.14, 136.78, 140.16, 140.90, 145.40, 150.98, 151.70,152.65, 153.30, 153.81. HRMS (ESI) m/z: calcd. for C₂₁H₁₇ClFN₆O:[M1+H]⁺=423.1131, found 423.1127. Anal. Calcd for C₂₁H₁₆ClFN₆O: C,59.65; H, 3.81; N, 19.88. Found: C, 59.80; H, 3.84; N, 19.64.

1-(6-Methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)-3-(4-(methylthio)phenyl)urea(18)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 1/1 of dichloromethane/ethyl acetate as the eluent.100 mg of compound 18 were obtained as a yellow solid. Yield 76%. M.p.229-231° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.45 (s, 3H), 2.66 (s,3H), 7.05 (t, 1H, J=7.3 Hz), 7.26 (d, 2H, J=8.5 Hz), 7.39 (t, 2H, J=7.7Hz), 7.47 (d, 2H, J=8.5 Hz), 7.99 (d, 2H, J=7.9 Hz), 8.30 (brs, 1H, D₂Oexch.), 8.55 (s, 1H), 8.66 (s, 1H), 9.24 (brs, 1H, D₂O exch.), 10.02(brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ 15.93, 21.91, 118.73,119.00, 122.16, 125.00, 127.79, 128.80, 130.22, 130.28, 131.51, 137.18,140.19, 140.81, 145.10, 150.87, 152.59, 153.43. HRMS (ESI) m/z: calcd.for C₂₂H₂₁N₆OS: [M1+H]⁺=417.1492, found 417.1484. Anal. Calcd forC₂₂H₂₀N₆OS: C, 63.44; H, 4.84; N, 20.18. Found: C, 63.63; H, 4.89; N,19.99.

1-(2,4-Dichlorophenyl)-3-(6-methyl-3-(phenylamino)pyrido[2,3-b]pyrazin-7-yl)urea(19)

This compound was synthesized according to the general proceduredescribed above. The product was purified by column chromatography,using a mixture of 7/3 of dichloromethane/ethyl acetate as the eluent.110 mg of compound 19 were obtained as a yellow solid. Yield 79%.M.p.>300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.68 (s, 3H), 7.05 (t,1H, J=7.3 Hz), 7.37-7.43 (m, 3H), 7.65 (d, 1H, J=2.3 Hz), 7.99 (d, 2H,J=7.9 Hz), 8.20 (d, 1H, J=8.9 Hz), 8.55 (s, 1H), 8.63 (s, 1H), 8.98-9.01(m, 2H, D₂O exch.), 10.04 (brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz,DMSO-d₆) δ 22.14, 118.78, 122.22, 122.90, 123.07, 125.99, 126.52,127.64, 128.65, 128.81, 130.07, 130.99, 135.08, 140.13, 140.93, 145.41,151.01, 152.44, 153.72. HRMS (ESI) m/z: calcd. for C₂₁H₁₇Cl₂N₆O:[M1+H]⁺=439.0835, found 439.0830. Anal. Calcd for C₂₁H₁₆Cl₂N₆O: C,57.42; H, 3.67; N, 19.13. Found: C, 57.31; H, 3.64; N, 19.29.

Synthesis Example 4

Step 1: General Procedure for the Synthesis of Nitro Derivatives 20-23

Compounds 20-23 were synthesized following an analogous syntheticprocedure to that described for the preparation of compound 6 (Step 5,Example 1), starting from chloro derivative 5 (320 mg, 1.43 mmol). Thecrude products were purified by column chromatography.

Ethyl 4-((6-methyl-7-nitropyrido[2,3-b]pyrazin-3-yl)amino)benzoate (20)

Eluent of purification: dichloromethane/methanol 100/5. Yield 98%.Yellow solid, m.p. 298-300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 1.33(t, 3H, J=7.1 Hz), 2.89 (s, 3H), 4.32 (q, 2H, J=7.1 Hz), 8.02 (d, 2H,J=8.5 Hz), 8.13 (d, 2H, J=8.5 Hz), 8.72 (s, 1H), 8.86 (s, 1H), 10.95(brs, 1H, D₂O exch.). HRMS (ESI) m/z calcd. for C₁₇H₁₆N₅O₄:[M1+H]⁺=354.1197, found 354.1191.

N-(3-((6-Methyl-7-nitropyrido[2,3-b]pyrazin-3-yl/amino/phenyl/acetamide(21)

Eluent of purification: dichioromethane/methanol 100/5. Yield 87%.Yellow solid, m.p.>300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.08 (s,3H), 2.88 (s, 3H), 7.27 (d, 1H, J=8.0 Hz), 7.36 (t, 1H, J=8.0 Hz), 7.97(d, 1H, J=8.0 Hz), 8.11 (s, 1H), 8.69 (s, 1H), 8.81 (s, 1H), 10.06 (brs,1H, D₂O exch.), 10.66 (brs, 1H, D₂O exch.). HRMS (ESI) m/z: calcd. forC₁₆H₁₅N₆O₃: [M1+H]⁺=339.1200, found 339.1194.

N-(4-((6-Methyl-7-nitropyrido[2,3-b]pyrazin-3-yl/amino/phenyl/acetamide(22)

Eluent of purification: dichioromethane/methanol 100/5. Yield 85%. Redsolid, m.p. 186-8° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.05 (s, 3H),2.87 (s, 3H), 7.64 (d, 2H, J=9.0 Hz), 7.94 (d, 2H, J=9.0 Hz), 8.74 (s,1H), 8.78 (s, 1H), 10.06 (brs, 1H, D₂O exch.), 10.92 (brs, 1H, D₂Oexch.). HRMS (ESI) m/z: calcd. for C₁₆H₁₅N₆O₃: [M1+H]⁺=339.1200, found339.1192.

6-Methyl-7-nitro-A-(3,4,5-trimethoxyphenyl/pyrido[2,3-A]pyrazin-3-amine(23)

Eluent of purification: dichioromethane/ethyl acetate 7/3. Yield 81%.Orange solid, m.p. 266-8° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.86(s, 3H), 3.68 (s, 3H), 3.83 (s, 6H), 7.36 (s, 2H), 8.60 (s, 1H), 8.78(s, 1H), 10.56 (brs, 1H, D₂O exch.). HRMS (ESI) m/z: calcd. forC₁₇H₁₈N₅O₅: [M1+H]⁺=372.1302, found 372.1294.

Step 2: General Procedure for the Synthesis of Aminoderivatives 24-27.

Compounds 24-27 were synthesized following an analogous syntheticprocedure to that described for the preparation of compound 7 (Step 6,Example 1), starting from nitro derivatives 20-23 (1.2 mmol),respectively. The crude products were purified by column chromatography.

Ethyl 4-((7-amino-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)benzoate (24)

Eluent of purification: dichloromethane/methanol 100/5. Yield 88%.Yellow solid, m.p. 257-9° C. (Et₂O). ¹H-NMR (600 MHz, DMSO-d₆) δ 1.32(t, 3H, J=7.1 Hz), 2.51 (s, 3H), 4.30 (q, 2H, J=7.1 Hz), 5.52 (brs, 2H,D₂O exch.), 7.29 (s, 1H), 7.96 (d, 2H, J=8.9 Hz), 8.06 (d, 2H, J=8.9Hz), 8.48 (s, 1H), 10.11 (brs, 1H, D₂O exch.). HRMS (ESI) m/z calcd. forC₁₇H₁₈N₅O₂: [M1+H]⁺=324.1455, found 324.1449.

N-(3-((7-Amino-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)phenyl)acetamide(25)

Eluent of purification: dichioromethane/methanol 100/5. Yield 81%.Orange solid, m.p. 239-241° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.06(s, 3H), 2.48 (s, 3H), 5.39 (brs, 2H, D₂O exch.), 7.15 (d, 1H, J=8.2Hz), 7.23-7.28 (m, 2H), 7.90 (d, 1H, J=8.0 Hz), 7.98 (s, 1H), 8.44 (s,1H), 9.70 (brs, 1H, D₂O exch.), 9.94 (brs, 1H, D₂O exch.). HRMS (ESI)m/z calcd. for C₁₆H₁₇N₆O: [M1+H]⁺=309.1458, found 309.1451.

N-(4-((7-Amino-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)phenyl)acetamide(26)

Eluent of purification: dichioromethane/methanol 100/6. Yield 66%.Orange solid, m.p. 275-7° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.03(s, 3H), 2.53 (s, 3H), 5.52 (brs, 2H, D₂O exch.), 7.44 (s, 1H), 7.57 (d,2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 8.50 (s, 1H), 9.93 (brs, 1H, D₂Oexch.), 10.03 (brs, 1H, D₂O exch.). HRMS (ESI) m/z calcd. for C₁₆H₁₇N₆O:[M1+H]⁺=309.1458, found 309.1455.

6-Methyl-N³-(3,4,5-trimethoxyphenyl)pyrido[2,3-b]pyrazine-3,7-diamine(27)

Eluent of purification: dichioromethane/methanol 100/4. Yield 68%.Yellow solid, m.p. 265-7° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.47(s, 3H), 3.65 (s, 3H), 3.81 (s, 6H), 5.38 (brs, 2H, D₂O exch.), 7.25 (s,1H), 7.33 (s, 2H), 8.37 (s, 1H), 9.81 (brs, 1H, D₂O exch.). HRMS (ESI)m/z: calcd. for C₁₇H₂₀N₅O₃: [M1+H]⁺=342.1561, found 342.1556.

Step 3: General Procedure for the Synthesis of Urea Derivatives 28-34.

Compounds 28-34 were synthesized following an analogous syntheticprocedure to that described for the preparation of derivatives 15-19(Step 1, Example 3), upon treatment of amines 24-27 (0.4 mmol) with3-chloro-4-fluorophenyl isocyanate (0.6 mmol) or3-(trifluoromethyl)phenyl isocyanate (0.6 mmol), respectively. The crudeproducts were purified by column chromatography.

Ethyl4-((7-(3-(3-chloro-4-fluorophenyl)ureido)-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)benzoate(28)

Eluent of purification: dichloromethane/methanol 100/5. Yield 96%.Yellow solid, m.p.>300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 1.33 (t,3H, J=7.1 Hz), 2.68 (s, 3H), 4.31 (q, 2H, J=7.1 Hz), 7.31-7.35 (m, 1H),7.37 (t, 1H, J=8.0 Hz), 7.87 (dd, 1H, J=6.8 Hz+2.5 Hz), 8.00 (d, 2H,J=8.8 Hz), 8.13 (d, 2H, J=8.8 Hz), 8.42 (brs, 1H, D₂O exch.), 8.62 (s,1H), 8.68 (s, 1H), 9.43 (brs, 1H, D₂O exch.), 10.44 (brs, 1H, D₂Oexch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ 14.27, 21.98, 60.31, 116.94,117.08, 117.87, 118.52, 118.56, 119.23, 119.35, 119.55, 122.83, 125.15,130.34, 130.74, 131.84, 136.73, 140.80, 144.61, 144.78, 150.37, 151.72,152.58, 153.32, 154.01, 165.47. HRMS (ESI) m/z: calcd. forC₂₄H₂₁ClFN₆O₃: [M1+H]⁺=495.1342, found 495.1338. Anal. Calcd forC₂₄H₂₀ClFN₆O₃: C, 58.25; H, 4.07; N, 16.98. Found: C, 58.42; H, 4.13; N,16.71.

Ethyl4-((6-methyl-7-(3-(3-(trifluoromethyl)phenyl)ureido)pyrido[2,3-b]pyrazin-3-yl)amino)benzoate(29)

Eluent of purification: dichioromethane/methanol 100/5. Yield 93%.Yellow solid, m.p.>300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 1.33 (t,3H, J=7.1 Hz), 2.70 (s, 3H), 4.31 (q, 2H, J=7.1 Hz), 7.35 (d, 1H, J=7.5Hz), 7.56 (t, 1H, J=7.9 Hz), 7.62 (d, 1H, J=8.4 Hz), 8.00 (d, 2H, J=8.8Hz), 8.05 (s, 1H), 8.13 (d, 2H, J=8.8 Hz), 8.46 (brs, 1H, D₂O exch.),8.62 (s, 1H), 8.70 (s, 1H), 9.60 (brs, 1H, D₂O exch.), 10.44 (brs, 1H,D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ 14.25, 22.00, 60.27, 114.05,117.85, 118.33, 121.77, 122.80, 123.27, 125.08, 125.20, 129.29, 129.50,129.70, 129.92, 130.05, 130.32, 130.72, 131.77, 140.33, 140.80, 144.60,144.80, 150.37, 152.62, 154.05, 165.43. HRMS (ESI) m/z: calcd. forC₂₅H₂₂F₃N₆O₃: [M1+H]⁺=511.1700, found 511.1692. Anal. Calcd forC₂₅H₂₁F₃N₆O₃: C, 58.82; H, 4.15; N, 16.46. Found: C, 59.04; H, 4.21; N,16.22.

N-(3-((7-(3-(3-Chloro-4-fluorophenyl)ureido)-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)phenyl)acetamide(30)

Eluent of purification: dichioromethane/methanol 100/6. Yield 90%.Orange solid, m.p. 225-7° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.08(s, 3H), 2.65 (s, 3H), 7.21 (d, 1H, J=8.2 Hz), 7.30 (t, 1H, J=8.2 Hz),7.32-7.38 (m, 2H), 7.86 (dd, 1H, J=6.8 Hz+2.5 Hz), 7.97 (d, 1H, J=8.2Hz), 8.04 (s, 1H), 8.40 (brs, 1H, D₂O exch.), 8.57 (s, 1H), 8.61 (s,1H), 9.45 (brs, 1H, D₂O exch.), 10.00 (brs, 1H, D₂O exch.), 10.05 (brs,1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ 21.92, 24.05, 109.70,113.43, 113.82, 116.93, 117.07, 118.48, 118.52, 119.21, 119.33, 119.51,125.74, 128.93, 130.16, 131.15, 136.83, 139.63, 140.34, 141.01, 145.40,151.03, 151.68, 152.69, 153.28, 153.76, 168.38. HRMS (ESI) m/z: calcd.for C₂₃H₂₀ClFN₇O₂: [M1+H]⁺=480.1346, found 480.1339. Anal. Calcd forC₂₃H₁₉ClFN₇O₂: C, 57.56; H, 3.99; N, 20.43. Found: C, 57.77; H, 4.04; N,20.30.

N-(3-((6-Methyl-7-(3-(3-(trifluoromethyl)phenyl)ureido)pyrido[2,3-b]pyrazin-3-yl)amino)phenyl)acetamide(31)

Eluent of purification: dichloromethane/methanol 100/6. Yield 94%.Orange solid, m.p. 218-220° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.08(s, 3H), 2.66 (s, 3H), 7.21 (d, 1H, J=8.6 Hz), 7.31 (t, 1H, J=8.1 Hz),7.35 (d, 1H, J=7.7 Hz), 7.55 (t, 1H, J=7.8 Hz), 7.61 (d, 1H, J=8.5 Hz),7.97 (d, 1H, J=8.2 Hz), 8.03-8.07 (m, 2H), 8.40 (brs, 1H, D₂O exch.),8.58 (s, 1H), 8.62 (s, 1H), 9.54 (brs, 1H, D₂O exch.), 10.00 (brs, 1H,D₂O exch.), 10.05 (brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ21.85, 24.05, 109.71, 113.45, 113.83, 114.13, 118.35, 121.83, 123.30,125.10, 125.93, 128.94, 129.32, 129.52, 129.73, 129.94, 130.08, 130.16,131.05, 139.64, 140.33, 140.39, 141.05, 145.48, 151.06, 152.70, 153.84,168.38. HRMS (ESI) m/z: calcd. for C₂₄H₂₁F₃N₇O₂: [M1+H]⁺=496.1703, found496.1699. Anal. Calcd for C₂₄H₂₀F₃N₇O₂: C, 58.18; H, 4.07; N, 19.79.Found: C, 58.01; H, 4.03; N, 19.94.

N-(4-((7-(3-(3-Chloro-4-fluorophenyl)ureido)-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)phenyl)acetamide(32)

Eluent of purification: dichioromethane/methanol 100/7. Yield 86%.Orange solid, m.p. 233-5° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.04(s, 3H), 2.65 (s, 3H), 7.31-7.39 (m, 2H), 7.59 (d, 2H, J=8.9 Hz), 7.86(dd, 1H, J=6.8 Hz+2.5 Hz), 7.90 (d, 2H, J=8.9 Hz), 8.37 (brs, 1H, D₂Oexch.), 8.52 (s, 1H), 8.59 (s, 1H), 9.41 (brs, 1H, D₂O exch.), 9.91(brs, 1H, D₂O exch.), 10.01 (brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz,DMSO-d₆) δ 21.82, 23.88, 116.92, 117.06, 118.38, 118.42, 119.19, 119.31,119.39, 119.58, 126.05, 130.03, 131.01, 134.19, 135.33, 136.90, 141.14,145.27, 145.33, 150.94, 151.63, 152.73, 153.23, 153.40, 167.91. HRMS(ESI) m/z: calcd. for C₂₃H₂₀ClFN₇O₂: [M1+H]⁺=480.1346, found 480.1342.Anal. Calcd for C₂₃H₁₉ClFN₇O₂: C, 57.56; H, 3.99; N, 20.43. Found: C,57.32; H, 3.90; N, 20.66.

N-(4-((6-Methyl-7-(3-(3-(trifluoromethyl)phenyl)ureido)pyrido[2,3-b]pyrazin-3-yl)amino)phenyl)acetamide(33)

Eluent of purification: dichloromethane/methanol 100/8. Yield 83%.Orange solid, m.p. 227-9° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.04(s, 3H), 2.66 (s, 3H), 7.34 (d, 1H, J=7.1 Hz), 7.55 (t, 1H, J=8.0 Hz),7.58-7.63 (m, 3H), 7.90 (d, 2H, J=8.9 Hz), 8.05 (s, 1H), 8.41 (brs, 1H,D₂O exch.), 8.53 (s, 1H), 8.60 (s, 1H), 9.58 (brs, 1H, D₂O exch.), 9.91(brs, 1H, D₂O exch.), 10.00 (brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz,DMSO-d₆) δ 21.71, 23.88, 113.99, 118.24, 119.25, 119.58, 121.70, 123.30,125.11, 126.40, 129.29, 129.50, 129.71, 129.92, 130.04, 130.96, 134.25,135.27, 140.47, 141.28, 145.27, 150.98, 152.78, 153.32, 167.92. HRMS(ESI) m/z: calcd. for C₂₄H₂₁F₃N₇O₂: [M1+H]⁺=496.1703, found 496.1695.Anal. Calcd for C₂₄H₂₀F₃N₇O₂: C, 58.18; H, 4.07; N, 19.79. Found: C,57.95; H, 4.01; N, 19.86.

1-(6-Methyl-3-((3,4,5-trimethoxyphenyl)amino)pyrido[2,3-b]pyrazin-7-yl)-3-(3-(trifluoromethyl)phenyl)urea(34)

Eluent of purification: dichioromethane/methanol 100/2. Yield 78%.Yellow solid, m.p. 222-4° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.65(s, 3H), 3.66 (s, 3H), 3.83 (s, 6H), 7.32-7.39 (m, 3H), 7.54 (t, 1H,J=7.5 Hz), 7.61 (d, 1H, J=7.6 Hz), 8.05 (s, 1H), 8.41 (brs, 1H, D₂Oexch.), 8.51 (s, 1H), 8.62 (s, 1H), 9.56 (brs, 1H, D₂O exch.), 9.97(brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ 22.10, 56.00, 60.22,97.37, 114.12, 118.34, 121.83, 123.30, 125.11, 125.83, 129.31, 129.53,129.74, 129.92, 130.09, 130.17, 131.04, 133.20, 136.19, 140.39, 140.82,145.44, 151.03, 152.70, 152.89, 153.86. HRMS (ESI) m/z: calcd. forC₂₅H₂₄F₃N₆O₄: [M1+H]⁺=529.1806, found 529.1799. Anal. Calcd forC₂₅H₂₃F₃N₆O₄: C, 56.82; H, 4.39; N, 15.90. Found: C, 57.07; H, 4.46; N,15.69.

Synthesis Example 5 Synthesis of carboxylic acids 35 and 36 Step 1:Synthesis of carboxylic acids 35 and 36

Sodium hydroxide aqueous solution (40% w/v, 2 mL) was added into asuspension of ethyl esters 28 or 29 (0.2 mmol, their synthesis isdescribed at Step 3 of Example 4) in ethanol (6 mL) and this mixture wasrefluxed for 2 hours. Upon completion of the reaction the solvent wasremoved under reduced pressure and the residue was acidified until pH=3,upon addition of a 2N hydrochloric acid solution. The precipitate wasfiltered under vacuum, washed with water and air-dried. The product wasthen purified by column chromatography.

4-((7-(3-(3-Chloro-4-fluorophenyl)ureido)-6-methylpyrido[2,3-b]pyrazin-3-yl)amino)benzoicacid (35)

Eluent of purification: dichloromethane/methanol 100/12. Yield 82%.Orange solid, m.p.>300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.69 (s,3H), 7.32-7.39 (m, 2H), 7.86 (dd, 1H, J=6.8 Hz+2.5 Hz), 7.98 (d, 2H,J=8.7 Hz), 8.11 (d, 2H, J=8.7 Hz), 8.50 (brs, 1H, D₂O exch.), 8.63 (s,1H), 8.70 (s, 1H), 9.55 (brs, 1H, D₂O exch.), 10.44 (brs, 1H, D₂Oexch.), 12.62 (v brs, 1H, D₂O exch.). ¹³C-NMR (151 MHz, DMSO-d₆) δ21.83, 116.93, 117.07, 117.87, 118.47, 118.52, 119.22, 119.34, 119.50,123.83, 125.49, 130.52, 130.67, 131.82, 136.75, 141.00, 144.24, 144.65,150.47, 151.71, 152.62, 153.30, 153.81, 167.05. HRMS (ESI) m/z: calcd.for C₂₂H₁₇ClFN₆O₃: [M1+H]⁺=467.1029, found 467.1022. Anal. Calcd forC₂₂H₁₆ClFN₆O₃: C, 56.60; H, 3.45; N, 18.00. Found: C, 56.83; H, 3.55; N,17.86.

4-((6-Methyl-7-(3-(3-(trifluoromethyl)phenyl)ureido)pyrido[2,3-b]pyrazin-3-yl)amino)benzoicacid (36)

Eluent of purification: dichioromethane/methanol 100/12. Yield 85%.Orange solid, m.p.>300° C. (EtOAc). ¹H-NMR (600 MHz, DMSO-d₆) δ 2.70 (s,3H), 7.35 (d, 1H, J=7.7 Hz), 7.56 (t, 1H, J=7.8 Hz), 7.63 (d, 1H, J=8.3Hz), 7.98 (d, 2H, J=8.8 Hz), 8.06 (s, 1H), 8.11 (d, 2H, J=8.8 Hz), 8.54(brs, 1H, D₂O exch.), 8.63 (s, 1H), 8.69 (s, 1H), 9.73 (brs, 1H, D₂Oexch.), 10.41 (brs, 1H, D₂O exch.), 12.62 (v brs, 1H, D₂O exch.).¹³C-NMR (151 MHz, DMSO-d₆) δ 22.54, 113.81, 117.80, 118.11, 121.54,123.34, 123.86, 124.82, 125.14, 129.30, 129.51, 129.71, 129.92, 130.00,130.48, 130.69, 131.93, 140.67, 140.89, 144.40, 144.74, 150.49, 152.93,153.96, 167.24. HRMS (ESI) m/z calcd. for C₂₃H₁₈F₃N₆O₃:[M1+H]⁺=483.1387, found 483.1380. Anal. Calcd for C₂₃H₁₇F₃N₆O₃: C,57.26; H, 3.55; N, 17.42. Found: C, 57.11; H, 3.51; N, 17.66.

Synthesis References

H. Ritter, H. Licht, Synthesis and reactions of dinitrated amino anddiaminopyridines, J. Heterocyclic Chem. 32 (1995) 585-590. N. Lougiakis,P. Marakos, N. Pouli, E. Fragopoulou, R. Tenta, Synthesis of newnebularine analogues and their inhibitory activity against adenosinedeaminase, Chem. Pharm. Bull. 63 (2015) 134-142. O. Argyros, N.Lougiakis, E. Kouvari, A. Papafotika, C. P. Raptopoulou, V. Psycharis,S. Christoforidis, N. Pouli, P. Marakos, C. Tamvakopoulos, Design andSynthesis of Novel 7-Aminosubstituted pyrido[2,3-6]pyrazines ExhibitingAnti-breast Cancer Activity, Eur. J. Med. Chem. (2017), 126, 954-968.

Example 3. Assay

MTS assays were performed for cell viability. To determine if novelpyridopyrazine derivatives have antitumor activities, compounds werescreened at 10 μM final concentration with A2058 melanoma and DU145prostate cancer cell lines. Compounds #16 and #17 were selected todetermine IC50 values against lung cancer cell lines, including A549,DMS273, H69, H513, H2461, DMS114, H358 and H2596. In this assay, cells(5000/well) were seeded in 96-well plates, incubated overnight at 37° C.in 5% CO₂, and exposed to 10 μM of compounds or in a dose-dependentmanner for 48 h. After 48 h treatment with compounds, MTS dye (20μL/well) was added to 96-well plates. Viable cell numbers weredetermined by tetrazolium conversion to its formazan dye. Absorbance wasmeasured at 490 nm using an automated ELISA plate reader. Dimethylsulfoxide (DMSO) was used as the vehicle control. Each experiment wasconducted in triplicate. IC50 values were determined using CalcuSynsoftware (Biosoft).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having the formula:

wherein, Ring A is an aryl or heteroaryl; R¹ is independently halogen,—CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B), —N(O)_(m1),—NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C), —C(O)NR^(1A)R^(1B),—OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),—NR^(1A)OR^(1C), —N₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is aninteger from 0 to 5; Ring B is an aryl or heteroaryl; R² isindependently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX²₂, —CN, —SO_(ll2)R^(2D), —SO_(v2)NR^(2A)R^(2B), —NHC(O)NR^(2A)R^(2B),—N(O)_(m2), —NR^(2A)R^(2B), —C(O)R^(2C), —C(O)—OR^(2C),—C(O)NR^(2A)R^(2B), —OR^(2D), —NR^(2A)SO₂R^(2D), —NR^(2A)C(O)R^(2C),—NR^(2A)C(O)OR^(2C), —NR^(2A)OR^(2C), —N₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; z2 is an integer from 0 to 5; R³ is independently hydrogen,—CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), —OR^(3A), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,—C(O)R^(4A), —C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; L is abond or —N(R⁵)—; R⁵ is independently hydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,—C(O)R^(5A), —C(O)OR^(5A), —C(O)NR^(5A)R^(5B), substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R⁶ isindependently hydrogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —C(O)R^(6A),—C(O)OR^(6A), —C(O)NR^(6A)R^(6B), substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl; R⁷ is independently hydrogen,—CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —C(O)R^(7A),—C(O)OR^(7A), —C(O)NR^(7A)R^(7B), —OR^(7A), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁸ is independently hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸ ₂, —CN, —C(O)R^(8A), —C(O)OR^(8A),—C(O)NR^(8A)R^(8B), —OR^(8A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; EachR^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(4A), R^(4B), R^(5A), R^(5B), R^(6A), R^(6B), R^(7A), R^(7B),R^(8A), and R^(8B) is independently hydrogen, —CX₃, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(2A) and R^(2B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(3A) and R^(3B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(5A) andR^(5B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(6A) and R^(6B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(8A) and R^(8B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X¹,X², X³, X⁴, X⁵, X⁶, X⁷, and X⁸ is independently —F, —Cl, —Br, or —I; n1and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2are independently 1 or
 2. 2. The compound of claim 1, wherein L is—N(R⁵)—.
 3. The compound of claim 1, wherein L is a bond.
 4. Thecompound of claim 1, wherein R⁸ is hydrogen, —CX⁸ ₃, —CHX⁸ ₂, —CH₂X⁸, orunsubstituted C₁-C₂ alkyl.
 5. The compound of claim 1, wherein R⁸ ishydrogen.
 6. The compound of claim 1, wherein R⁷ is hydrogen, —CX⁷ ₃,—CHX⁷ ₂, —CH₂X⁷, or unsubstituted C₁-C₂ alkyl.
 7. The compound of claim1, wherein R⁷ is hydrogen.
 8. The compound of claim 1 having theformula:


9. The compound of claim 1, wherein R⁶ is hydrogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, or unsubstituted C₁-C₂ alkyl.
 10. The compound of claim 1,wherein R⁶ is hydrogen.
 11. The compound of claim 1, wherein R⁵ ishydrogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, or unsubstituted C₁-C₂ alkyl.
 12. Thecompound of claim 1, wherein R⁵ is hydrogen.
 13. The compound of claim1, wherein R⁴ is hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, or unsubstitutedC₁-C₂ alkyl.
 14. The compound of claim 1, wherein R⁴ is hydrogen. 15.The compound of claim 1, wherein R³ is —CX³ ₃, —CHX³ ₂, —CH₂X³, orunsubstituted C₁-C₃ alkyl.
 16. The compound of claim 1, wherein R³ isunsubstituted methyl.
 17. The compound of claim 1 having the formula:


18. The compound of claim 1, wherein Ring A is a phenyl or 5 to 6membered heteroaryl.
 19. The compound of claim 1, wherein Ring A is aphenyl.
 20. The compound of claim 1, wherein R¹ is independentlyhalogen, —CX³ ₃, —CHX¹ ₂, —CH₂X′, —SCX′₃, —SCHX^(1D), —SCH₂X′,unsubstituted C₁-C₂ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.21. The compound of claim 1, wherein R¹ is independently halogen, —CX³₃, —CHX^(1D), —CH₂X′, or unsubstituted C₁-C₂ alkyl.
 22. The compound ofclaim 1, wherein R¹ is independently halogen, —CF₃, —CHF₂, —CH₂F, —CH₃,—SCF₃, —SCHF₂, —SCH₂F, or —SCH₃.
 23. The compound of claim 1, wherein R¹is independently halogen, —CX³ ₃, or —SCH₃.
 24. The compound of claim 1,wherein R¹ is independently —F, —Cl, —SCH₃, or —CF₃.
 25. The compound ofclaim 1, wherein z1 is
 2. 26. The compound of claim 1, wherein z1 is 1.27. The compound of claim 1, wherein z1 is
 0. 28. The compound of claim1 having the formula:


29. The compound of claim 1 having the formula:


30. The compound of claim 1 having the formula:


31. The compound of claim 1 having the formula:


32. The compound of claim 1, wherein Ring B is a phenyl or 5 to 6membered heteroaryl.
 33. The compound of claim 1, wherein Ring B is aphenyl.
 34. The compound of claim 1, wherein R² is independently —OCX²₃, —OCH₂X², —OCHX² ₂, —C(O)R^(2C), —C(O)OR^(2C), —OR^(2D), or—NR^(2A)C(O)R^(2C); and Each R^(2A), R^(2B), R^(2C), and R^(2D) isindependently hydrogen, —CX₃, —CHX₂, —CH₂X, unsubstituted C₁-C₂ alkyl.35. The compound of claim 1, wherein R² is independently —OCF₃, —OCH₂F,—OCHF₂, —C(O)OH, —C(O)OCH₂CH₃, —OCH₃, or —NHC(O)CH₃.
 36. The compound ofclaim 1, wherein z2 is
 3. 37. The compound of claim 1, wherein z2 is 2.38. The compound of claim 1, wherein z2 is
 1. 39. The compound of claim1, wherein z2 is
 0. 40. The compound of claim 38 having the formula:


41. The compound of claim 38 having the formula:


42. The compound of claim 39 having the formula:


43. The compound of claim 38 having the formula:


44. The compound of claim 38 having the formula:


45. The compound of claim 39 having the formula:


46. The compound of claim 38 having the formula:


47. The compound of claim 38 having the formula:


48. The compound of claim 39 having the formula:


49. The compound of claim 38 having the formula:


50. The compound of claim 38 having the formula:


51. The compound of claim 39 having the formula:


52. A pharmaceutical composition comprising a compound of one of claims1 to 51 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 53. The pharmaceuticalcomposition of claim 52, comprising a therapeutically effective amountof said compound.
 54. A method of treating cancer, said methodcomprising administering to a subject in need thereof an effectiveamount of a compound of one of claims 1 to
 51. 55. The method of claim54, wherein the cancer is lung cancer.
 56. The method of claim 54,wherein the cancer is small cell lung cancer.
 57. The method of claim54, wherein the cancer is non-small cell lung cancer.
 58. The method ofclaim 54, wherein the cancer is prostate cancer.
 59. The method of claim54, wherein the cancer is hormone sensitive prostate cancer.
 60. Themethod of claim 54, wherein the cancer is hormone refractory prostatecancer.
 61. The method of claim 54, wherein the cancer is melanoma. 62.The method of claim 54, wherein the cancer is lung cancer, prostatecancer, melanoma, lymphoma, sarcoma, breast cancer, ovarian cancer,pancreatic cancer, bladder cancer, bone cancer, brain cancer, cervicalcancer, colorectal cancer, esophageal cancer, gastric cancer, livercancer, head and neck cancer, kidney cancer, myeloma, leukemia, orthyroid cancer.